Macrocyclic immunomodulators

ABSTRACT

Compounds are provided that are useful as immunomodulators. The compounds have the following Formula (I) or (II): 
     
       
         
         
             
             
         
       
         
         
           
             including stereoisomers and pharmaceutically acceptable salts thereof, wherein R, R 1 , R 2a , R 2b , R 2c , R 3 , R 4 , R 5 , R 6a , R 6b , R 6c , m and n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 62/542,694 filed Aug. 8, 2017, the contents of which is incorporatedherein by reference in its entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

NOT APPLICABLE

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

NOT APPLICABLE

BACKGROUND OF THE DISCLOSURE

Programmed cell death protein-1 (PD-1) is a member of the CD28superfamily that delivers negative signals upon interaction with its twoligands, PD-L1 or PD-L2. PD-1 and its ligands are broadly expressed andexert a wide range of immunoregulatory roles in T cells activation andtolerance. PD-1 and its ligands are involved in attenuating infectiousimmunity and tumor immunity, and facilitating chronic infection andtumor progression.

Modulation of the PD-1 pathway has therapeutic potential in varioushuman diseases (Hyun-Tak Jin et al., Curr Top Microbiol Immunol. (2011);350:17-37). Blockade of the PD-1 pathway has become an attractive targetin cancer therapy. Therapeutic antibodies that block the programmed celldeath protein-1 (PD-1) immune checkpoint pathway prevent T-cell downregulation and promote immune responses against cancer. Several PD-1pathway inhibitors have shown robust activity in various phases ofclinical trials (RD Harvey, Clinical Pharmacology and Therapeutics(2014); 96(2), 214-223).

Accordingly, agents that block the interaction of PD-L1 with either PD-1or CD80 are desired. Some antibodies have been developed andcommercialized. However there is still a need for alternative compoundssuch as small molecules which may have advantageous characteristics interm of oral administration, stability, bioavailability, therapeuticindex, and toxicity. A few patent applications disclosing non-peptidicsmall molecules have been published (WO 2015/160641, WO 2015/034820, WO2017/066227, WO 2018/00905, WO 2018/044963, and WO 2018/118848 from BMS;WO 2015/033299, WO 2015/033301, WO 2016/142886, WO 2016/142894, WO2018/051254, and WO 2018/051255 from Aurigene; WO 2017/070089, US2017/0145025, WO 2017/106634, US2017/0174679, US 2017/0107216, WO2017/112730, WO 2017/192961, WO 2017/205464, WO 2017/222976, WO2018/013789, WO 2018/044783, WO 2018/119221, WO 2018/119224, WO2018/119236, WO 2018/119263, WO 2018/119266, and WO 2018/119286 fromIncyte) However, there remains a need for alternative small moleculesuseful as inhibitors of the PD-1 pathway.

BRIEF SUMMARY OF THE DISCLOSURE

In one aspect, provided herein are compounds having the Formula (I) or(II):

or a pharmaceutically acceptable salt thereof, wherein R, R¹, R^(2a),R^(2b), R^(2c), R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c), m and n are asdefined herein.

In addition to the compounds provided herein, the present disclosurefurther provides pharmaceutical compositions containing one or more ofthese compounds, as well as methods associated with preparation and useof such compounds. In some embodiments, the compounds are used intherapeutic methods to treat diseases associated with the PD-1/PD-L1pathway.

BRIEF DESCRIPTION OF THE DRAWINGS

NOT APPLICABLE

DETAILED DESCRIPTION OF THE DISCLOSURE Abbreviation and Definitions

The terms “a,” “an,” or “the” as used herein not only include aspectswith one member, but also include aspects with more than one member. Forinstance, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a cell” includes a plurality of such cells andreference to “the agent” includes reference to one or more agents knownto those skilled in the art, and so forth.

The terms “about” and “approximately” shall generally mean an acceptabledegree of error for the quantity measured given the nature or precisionof the measurements. Typical, exemplary degrees of error are within 20percent (%), preferably within 10%, and more preferably within 5% of agiven value or range of values. Alternatively, and particularly inbiological systems, the terms “about” and “approximately” may meanvalues that are within an order of magnitude, preferably within 5-foldand more preferably within 2-fold of a given value. Numerical quantitiesgiven herein are approximate unless stated otherwise, meaning that theterm “about” or “approximately” can be inferred when not expresslystated.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbon group,having the number of carbon atoms designated (i.e. C₁₋₈ means one toeight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group having one or more double bonds. Similarly,the term “alkynyl” refers to an unsaturated alkyl group having one ormore triple bonds. Examples of alkenyl groups include vinyl, 2-propenyl,crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl and3-(1,4-pentadienyl). Examples of alkynyl groups include ethynyl, 1- and3-propynyl, 3-butynyl, and the higher homologs and isomers. The term“cycloalkyl” refers to hydrocarbon rings having the indicated number ofring atoms (e.g., C₃₋₆cycloalkyl) and being fully saturated or having nomore than one double bond between ring vertices. “Cycloalkyl” is alsomeant to refer to bicyclic and polycyclic hydrocarbon rings such as, forexample, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The bicyclicor polycyclic rings may be fused, bridged, spiro or a combinationthereof. The term “heterocycloalkyl” or “heterocyclyl” refers to acycloalkyl group that contain from one to five heteroatoms selected fromN, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Theheterocycloalkyl may be a monocyclic, a bicyclic or a polycylic ringsystem. The bicyclic or polycyclic rings may be fused, bridged, spiro ora combination thereof. It is understood that the recitation for C₄₋₁₂heterocyclyl, refers to a group having from 4 to 12 ring members whereat least one of the ring members is a heteroatom. Non limiting examplesof heterocycloalkyl groups include pyrrolidine, imidazolidine,pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin,dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide,piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone,tetrahydrofuran, tetrhydrothiophene, quinuclidine, and the like. Aheterocycloalkyl group can be attached to the remainder of the moleculethrough a ring carbon or a heteroatom.

The term “alkylene” by itself or as part of another substituent means adivalent group derived from an alkane, as exemplified by —CH₂CH₂CH₂CH₂—.Typically, an alkyl (or alkylene) group will have from 1 to 12 carbonatoms, with those groups having 8 or fewer carbon atoms being preferredin the present disclosure. Similarly, “alkenylene” and “alkynylene”refer to the unsaturated forms of “alkylene” having double or triplebonds, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon group, or combinations thereof, consisting of thestated number of carbon atoms and from one to three heteroatoms selectedfrom the group consisting of O, N, Si and S, and wherein the nitrogenand sulfur atoms may optionally be oxidized and the nitrogen heteroatommay optionally be quaternized. The heteroatom(s) O, N and S may beplaced at any interior position of the heteroalkyl group. The heteroatomSi may be placed at any position of the heteroalkyl group, including theposition at which the alkyl group is attached to the remainder of themolecule. Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the terms“heteroalkenyl” and “heteroalkynyl” by itself or in combination withanother term, means, unless otherwise stated, an alkenyl group oralkynyl group, respectively, that contains the stated number of carbonsand having from one to three heteroatoms selected from the groupconsisting of O, N, Si and S, and wherein the nitrogen and sulfur atomsmay optionally be oxidized and the nitrogen heteroatom may optionally bequaternized. The heteroatom(s) O, N and S may be placed at any interiorposition of the heteroalkyl group.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent group, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH═CH—, —CH₂—CH═C(H)CH₂—O—CH₂— and—S—CH₂—C≡C—. For heteroalkylene groups, heteroatoms can also occupyeither or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like).

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Additionally, for dialkylaminogroups, the alkyl portions can be the same or different and can also becombined to form a 3-7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “hydroxyalkyl” or “alkyl-OH” refers to an alkyl group, asdefined above, where at least one of the hydrogen atoms is replaced witha hydroxy group. As for the alkyl group, hydroxyalkyl groups can haveany suitable number of carbon atoms, such as C₁₋₆. Exemplaryhydroxyalkyl groups include, but are not limited to, hydroxymethyl,hydroxyethyl (where the hydroxy is in the 1- or 2-position),hydroxypropyl (where the hydroxy is in the 1-, 2- or 3-position), etc.

The term “C₁₋₃ alkyl-guanidinyl” refers to a C₁₋₃ alkyl group, asdefined above, where at least one of the hydrogen atoms is replaced witha guanidinyl group (—NHC(NH)NH₂).

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to five heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. It is understoodthat the recitation for C₅₋₁₀ heteroaryl, refers to a heteroaryl moietyhaving from 5 to 10 ring members where at least one of the ring membersis a heteroatom. Non-limiting examples of aryl groups include phenyl,naphthyl and biphenyl, while non-limiting examples of heteroaryl groupsinclude pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl,quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl,benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl,benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl,thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,pyrrolyl, thiazolyl, furyl, thienyl and the like. Substituents for eachof the above noted aryl and heteroaryl ring systems are selected fromthe group of acceptable substituents described below.

The term “carbocyclic ring” “carbocyclic” or “carbocyclyl” refers tocyclic moieties with only carbon atoms as ring vertices. Carbocyclicring moieties are saturated or unsaturated and can be aromatic.Generally, carbocyclic moieties have from 3 to 10 ring members.Carbocylic moieties with multiple ring structure (e.g. bicyclic) caninclude a cycloalkyl ring fused to a aromatic ring (e.g.1,2,3,4-tetrahydronaphthalene). Thus, carboclicic rings includecyclopentyl, cyclohexenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl. Theterm “heterocyclic ring” refers to both “heterocycloalkyl” and“heteroaryl” moieties. Thus, heterocyclic rings are saturated orunsaturated and can be aromatic. Generally, heterocyclic rings are 4 to10 ring members and include piperidinyl, tetrazinyl, pyrazolyl andindolyl.

When any of the above terms (e.g., “alkyl,” “aryl” and “heteroaryl”) arereferred to as ‘substituted’ without further notation on thesubstituents, the substituted forms of the indicated group will be asprovided below.

Substituents for the alkyl groups (including those groups often referredto as alkylene, alkenyl, alkynyl and cycloalkyl) can be a variety ofgroups selected from: -halogen, —OR′, —NR′R″, —SR′, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —CN and—NO₂ in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such group. R′, R″ and R′″ each independentlyrefer to hydrogen, unsubstituted C₁₋₈ alkyl, unsubstituted heteroalkyl,unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstitutedC₁₋₈ alkyl, C₁₋₈ alkoxy or C₁₋₈ thioalkoxy groups, or unsubstitutedaryl-C₁₋₄ alkyl groups. When R′ and R″ are attached to the same nitrogenatom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-,6-, or 7-membered ring. For example, —NR′R″ is meant to include1-pyrrolidinyl and 4-morpholinyl. The term “acyl” as used by itself oras part of another group refers to an alkyl group wherein twosubstitutents on the carbon that is closest to the point of attachmentfor the group is replaced with the substitutent ═O (e.g., —C(O)CH₃,—C(O)CH₂CH₂OR′ and the like).

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′,—R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′,—NR″C(O)₂R′, —NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C₁₋₄ alkyl, andunsubstituted aryloxy-C₁₋₄ alkyl. Other suitable substituents includeeach of the above aryl substituents attached to a ring atom by analkylene tether of from 1-4 carbon atoms.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerof from 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

As used herein the term “macrocycle” refers to a cyclic chemicalstructure having 12 to 20 atoms as ring vertices. Suitable ring verticesinclude carbon, nitrogen, oxygen, and sulfur. Macrocyclic rings mayinclude one or more ring structures such as a phenyl, cycloalkyl,heteroaryl, or heterocycloalkyl group. When assigning a size of themacrocyclic ring, excocyclic atoms are not included in thedetermination. For example when a pyridine with meta linkages comprisepart of the macrocylic ring, only the three atoms that act as ringvertices in the macroclic ring are included.

Similarly, when a phenyl ring with ortho linkages comprises part of themacrocyclic ring, only the two atoms that acts as ring vertices in themacrocylic ring are included.

The term “natural amino acid” refers to the 20 common naturallyoccurring amino acids as well as selenocystine or pyrrolosine.

The term “non-natural amino acid” refers to an amino acid that has amodified alpha carbon substituent such that it is not one of thenaturally occurring amino acids. In some embodiments non-natural aminoacids have an alpha carbon substituent selected from the groupconsisting of C₂₋₄ hydroxyalkyl, C₁₋₃ alkyl-guanidinyl, and C₁₋₄alkyl-heteroaryl.

The terms “patient” and “subject” include primates (especially humans),domesticated companion animals (such as dogs, cats, horses, and thelike) and livestock (such as cattle, pigs, sheep, and the like).

As used herein, the term “treating” or “treatment” encompasses bothdisease-modifying treatment and symptomatic treatment, either of whichmay be prophylactic (i.e., before the onset of symptoms, in order toprevent, delay or reduce the severity of symptoms) or therapeutic (i.e.,after the onset of symptoms, in order to reduce the severity and/orduration of symptoms).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present disclosurecontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentdisclosure contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentdisclosure contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present disclosure.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and are intendedto be encompassed within the scope of the present disclosure. Certaincompounds of the present disclosure may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present disclosure and are intended to bewithin the scope of the present disclosure.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. When a stereochemical depiction is shown, it is meantto refer to the compound in which one of the isomers is present andsubstantially free of the other isomer. ‘Substantially free of’ anotherisomer indicates at least an 80/20 ratio of the two isomers, morepreferably 90/10, or 95/5 or more. In some embodiments, one of theisomers will be present in an amount of at least 99%.

The compounds of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areintended to be encompassed within the scope of the present disclosure.For example, the compounds may be prepared such that any number ofhydrogen atoms are replaced with a deuterium (²H) isotope. The compoundsof the present disclosure may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. Unnatural proportions of an isotope may be defined as rangingfrom the amount found in nature to an amount consisting of 100% of theatom in question. For example, the compounds may incorporate radioactiveisotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C), or non-radioactive isotopes, such as deuterium (²H) orcarbon-13 (¹³C). Such isotopic variations can provide additionalutilities to those described elsewhere within this application. Forinstance, isotopic variants of the compounds of the disclosure may findadditional utility, including but not limited to, as diagnostic and/orimaging reagents, or as cytotoxic/radiotoxic therapeutic agents.Additionally, isotopic variants of the compounds of the disclosure canhave altered pharmacokinetic and pharmacodynamic characteristics whichcan contribute to enhanced safety, tolerability or efficacy duringtreatment. All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are intended to be encompassedwithin the scope of the present disclosure.

Compounds

In one aspect, the present disclosure provides compounds having Formula(I) or (II):

or a pharmaceutically acceptable salt thereof, wherein:

-   R is selected from the group consisting of H, halogen, CN, C₁₋₃    haloalkyl, C₁₋₃ alkyl and C₁₋₃ alkoxy;-   R¹ is selected from the group consisting of halogen, C₅₋₈    cycloalkyl, C₆₋₁₀ aryl and thienyl, wherein the C₆₋₁₀ aryl and    thienyl are optionally substituted with 1 to 5 R^(1a) substituents;-   each R^(1a) is independently selected from the group consisting of    halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),    —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c),    —NR^(a)—C(O)NR^(a)R^(b), —NR^(a)R^(b), —OR^(a), —O—X¹—OR^(a),    —O—X¹—CO₂R^(a), —O—X¹—CONR^(a)R^(b), —X¹—OR^(a), —X¹—NR^(a)R^(b),    —X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), —SF₅, and —S(O)₂NR^(a)R^(b),    wherein each X¹ is a C₁₋₄ alkylene; each R^(a) and R^(b) is    independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈    haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O or S, wherein the five or six-membered ring is optionally    substituted with oxo; each R^(c) is independently selected from the    group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl and C₁₋₈    haloalkyl; and optionally when two R^(1a) substituents are on    adjacent atoms, they are combined to form a fused five, six or    seven-membered carbocyclic or heterocyclic ring optionally    substituted with from 1 to 3 substituents independently selected    from halogen, oxo, C₁₋₈ haloalkyl and C₁₋₈ alkyl; or-   R¹ is

wherein

-   each of R^(1b), R^(1c), R^(1d) and R^(1e) is independently selected    from the group consisting of H, halogen, CF₃, CN, C₁₋₄ alkyl and    —O—C₁₋₄ alkyl, wherein the C₁₋₄ alkyl and —O—C₁₋₄ alkyl are    optionally further substituted with halogen, hydroxyl, methoxy or    ethoxy;-   L is a linking group selected from the group consisting of:

-   wherein each of the subscripts q is independently 1, 2, 3 or 4, and    L is optionally further substituted with one or two members selected    from the group consisting of halogen, hydroxy, C₁₋₃ alkyl, —O—C₁₋₃    alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ haloalkyl and —CO₂H;-   Z is selected from the group consisting of azetidinyl, pyrollidinyl,    piperidinyl, morpholinyl, pyridyl, pyrimidinyl, guanidinyl,    quinuclidine, and 8-azabicyclo[3.2.1]octane, each of which is    optionally substituted with from 1 to 3 groups independently    selected from halogen, hydroxy, C₁₋₃ alkyl, —NH₂, —NHC₁₋₃alkyl,    —N(C₁₋₃alkyl)₂, —O—C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ haloalkyl and    —CO₂H;-   or-   Z is selected from the group consisting of —CO₂R^(z1) and    —NR^(z1)R^(z2); wherein R^(z1) is selected from the group consisting    of H, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ hydroxyalkyl; and R^(z2)    is selected from —C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkyl-COOH, C₁₋₈    alkyl-OH, C₁₋₈ alkyl-CONH₂, C₁₋₈ alkyl-SO₂NH₂, C₁₋₈ alkyl-PO₃H₂,    C₁₋₈ alkyl-C(O)NHOH, —C(O)—C₁₋₈alkyl-OH, —C(O)—C₁₋₈alkyl-COOH, C₃₋₁₀    cycloalkyl, —C₃₋₁₀ cycloalkyl-COOH, —C₃₋₁₀ cycloalkyl-OH, C₄₋₈    heterocyclyl, —C₄₋₈ heterocyclyl-COOH, —C₄₋₈ heterocyclyl-OH, —C₁₋₈    alkyl-C₄₋₈ heterocyclyl, —C₁₋₈ alkyl-C₃₋₁₀ cycloalkyl, C₅₋₁₀    heteroaryl and —C₁₋₈alkyl-C₅₋₁₀ heteroaryl;-   each R^(2a), R^(2b) and R^(2c) is independently selected from the    group consisting of H, halogen, —CN, —R^(d), —CO₂R^(e),    —CONR^(e)R^(f), —OC(O)NR^(e)R^(f), —NR^(f)C(O)R^(e),    —NR^(f)C(O)₂R^(d), —NR^(e)—C(O)NR^(e)R^(f), —NR^(e)R^(f), —OR^(e),    —X²—OR^(e), —X²—NR^(e)R^(f), —X²—CO₂R^(e), —SF₅, and    —S(O)₂NR^(e)R^(f), wherein each X² is a C₁₋₄ alkylene; each R^(e)    and R^(f) is independently selected from hydrogen, C₁₋₈ alkyl, and    C₁₋₈ haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O and S, and optionally substituted with oxo; each R^(d) is    independently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈    alkenyl, and C₁₋₈ haloalkyl;-   R³ is selected from the group consisting of —NR^(g)R^(h) and C₄₋₁₂    heterocyclyl, wherein the C₄₋₁₂ heterocyclyl is optionally    substituted with 1 to 6 R^(3a);-   each R^(3a) is independently selected from the group consisting of    halogen, —CN, —R^(i), —CO₂R^(j), —CONR^(j)R^(k), —CONHC₁₋₆ alkyl-OH,    —C(O)R^(j), —OC(O)NR^(j)R^(k), —NR^(j)C(O)R^(k), —NR^(j)C(O)₂R^(k),    —CONHOH, —PO₃H₂, —NR^(j)—X³—C(O)₂R^(k), —NR^(j)C(O)NR^(j)R^(k),    —NR^(j)R^(k), —OR^(j), —S(O)₂NR^(j)R^(k), —O—X³—OR^(j),    —O—X³—NR^(j)R^(k), —O—X³—CO₂R^(j), —O—X³—CONR^(j)R^(k), —X³—OR^(j),    —X³—NR^(j)R^(k), —X³—CO₂R^(j), —X³—CONR^(j)R^(k), —X³—CONHSO₂R^(j)    and SF₅; wherein X³ is C₁₋₆ alkylene and is optionally further    substituted with OH, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂, COO—C₁₋₈alkyl    or CO₂H, wherein each R^(j) and R^(k) is independently selected from    hydrogen, C₁₋₈ alkyl optionally substituted with 1 to 2 substituents    selected from OH, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂, B(OH)₂,    COO—C₁₋₈alkyl or CO₂H, and C₁₋₈ haloalkyl optionally substituted    with 1 to 2 substituents selected from OH, SO₂NH₂, CONH₂, C(O)NHOH,    PO₃H₂, COO—C₁₋₈alkyl or CO₂H, or when attached to the same nitrogen    atom R^(j) and R^(k) can be combined with the nitrogen atom to form    a five or six-membered ring having from 0 to 2 additional    heteroatoms as ring members selected from N, O or S, and optionally    substituted with oxo; each R^(i) is independently selected from the    group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl    each of which may be optionally substituted with OH, SO₂NH₂, CONH₂,    C(O)NHOH, PO₃H₂, COO—C₁₋₈alkyl or CO₂H;-   R^(g) is selected from the group consisting of H, C₁₋₈ haloalkyl and    C₁₋₈ alkyl;-   R^(h) is selected from C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈    hydroxyalkyl, C₁₋₈alkyl-CO₂R, C₁₋₈alkyl-CONR^(j)R^(k),    C₁₋₈alkyl-CONHSO₂R^(j), C₁₋₈ alkyl-SO₂NR^(j)R^(k), C₁₋₈ alkyl-PO₃H₂,    C₁₋₈ alkyl-C(O)NHOH, C₁₋₈ alkyl-NR^(j)R^(k), —C(O)R_(j), C₃₋₁₀    cycloalkyl, —C₃₋₁₀ cycloalkyl-COOR^(j), —C₃₋₁₀ cycloalkyl-OR^(j),    C₄₋₈ heterocyclyl, —C₄₋₈ heterocyclyl-COOR^(j), —C₄₋₈    heterocyclyl-OR^(j), —C₁₋₈ alkyl-C₄₋₈ heterocyclyl, —C(═O)OC₁₋₈    alkyl-C₄₋₈ heterocyclyl, —C₁₋₈ alkyl-C₃₋₁₀ cycloalkyl, C₅₋₁₀    heteroaryl, —C₁₋₈alkyl-C₅₋₁₀ heteroaryl, —C₁₋₈ alkyl-C₆₋₁₀ aryl,    —C₁₋₈ alkyl-(C═O)—C₆₋₁₀ aryl, —CO₂—C₁₋₈ alkyl-O₂C—C₁₋₈ alkyl, —C₁₋₈    alkyl-NH(C═O)—C₂₋₈ alkenyl, —C₁₋₈ alkyl-NH(C═O)—C₁₋₈ alkyl, —C₁₋₈    alkyl-NH(C═O)—C₂₋₈ alkynyl, —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈    alkyl-COOR^(j), and —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-OR^(j)    optionally substituted with CO₂H; or    -   R^(h) combined with the N to which it is attached is a mono-,        di- or tri-peptide comprising 1-3 natural amino acids and 0-2        non-natural amino acids, wherein    -   the non-natural aminoacids have an alpha carbon substituent        selected from the group consisting of C₂₋₄ hydroxyalkyl, C₁₋₃        alkyl-guanidinyl, and C₁₋₄ alkyl-heteroaryl,    -   the alpha carbon of each natural or non-natural amino acid is        optionally further substituted with a methyl group, and    -   the terminal moiety of the mono-, di-, or tri-peptide is        selected from the group consisting of C(O)OH, C(O)O—C₁₋₆ alkyl,        and PO₃H₂, wherein    -   the C₁₋₈ alkyl portions of R^(h) are optionally further        substituted with from 1 to 3 substituents independently selected        from OH, COOH, SO₂NH₂, CONH₂, C(O)NHOH, COO—C₁₋₄ alkyl, PO₃H₂        and C₅₋₆ heteroaryl optionally substituted with 1 to 2 C₁-3        alkyl substituents,    -   the C₅₋₁₀ heteroaryl and the C₆₋₁₀ aryl portions of R^(h) are        optionally substituted with 1 to 3 substituents independently        selected from OH, B(OH)₂, COOH, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂,        COO—C₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄alkyl-OH, C₁₋₄alkyl-SO₂NH₂,        C₁₋₄alkyl CONH₂, C₁₋₄alkyl-C(O)NHOH, C₁₋₄alkyl-PO₃H₂,        C₁₋₄alkyl-COOH, and phenyl;    -   the C₄₋₈ heterocyclyl and C₃₋₁₀ cycloalkyl portions of R^(h) are        optionally substituted with 1 to 4 R^(h1) substituents;-   each R^(h1) substituent is independently selected from C₁₋₄ alkyl,    C₁₋₄ alkyl-OH, C₁₋₄ alkyl-COOH, C₁₋₄ alkyl-SO₂NH₂, C₁₋₄ alkyl CONH₂,    C₁₋₄ alkyl-C(O)NHOH, C₁₋₄ alkyl-PO₃H, OH, COO—C₁₋₈ alkyl, COOH,    SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂, B(OH)₂ and oxo;-   R⁴ is selected from the group consisting of O—C₁₋₈ alkyl, O—C₁₋₈    haloalkyl, C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, —O—C₁₋₄ alkyl-C₄₋₇    heterocycloalkyl, —O—C₁₋₄ alkyl-C₆₋₁₀aryl and —O—C₁₋₄ alkyl-C₅₋₁₀    heteroaryl, each of which is optionally substituted with 1 to 5    R^(4a);-   each R^(4a) is independently selected from the group consisting of    halogen, —CN, —R^(m), —CO₂R^(n), —CONR^(n)R^(p), —C(O)R^(n),    —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),    —NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —O—X⁴—OR^(n),    —O—X⁴—NR^(n)R^(p), —O—X⁴—CO₂R^(n), —O—X⁴—CONR^(n)R^(p), —X⁴—OR^(n),    —X⁴—NR^(n)R^(p), —X⁴—CO₂R^(n), —X⁴—CONR^(n)R^(p), —SF₅,    —S(O)₂R^(n)R^(p), —S(O)₂NR^(n)R^(p), C₃₋₇ cycloalkyl and C₄₋₇    heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl rings    are optionally substituted with 1 to 5 R^(t), wherein each R^(t) is    independently selected from the group consisting of C₁₋₈ alkyl,    C₁₋₈haloalkyl, —CO₂R^(n), —CONR^(n)R^(p), —C(O)R^(n),    —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),    —NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —O—X⁴—OR^(n),    —O—X⁴—NR^(n)R^(p), —O—X⁴—CO₂R^(n), —O—X⁴—CONR^(n)R^(p), —X⁴—OR^(n),    —X⁴—NR^(n)R^(p), —X⁴—CO₂R^(n), —X⁴—CONR^(n)R^(p), —SF₅, and    —S(O)₂NR^(n)R^(p);-   wherein each X⁴ is a C₁₋₆ alkylene; each R^(n) and R^(p) is    independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈    haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O or S, and optionally substituted with oxo; each R^(m) is    independently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈    alkenyl, and C₁₋₈ haloalkyl; and optionally when two R^(4a)    substituents are on adjacent atoms, they are combined to form a    fused five or six-membered carbocyclic or heterocyclic ring    optionally substituted with oxo;-   and wherein R³ and R⁴ are joined to form a 12- to 20-membered    macrocycle;-   n is 0, 1, 2 or 3;-   each R⁵ is independently selected from the group consisting of    halogen, —CN, —R^(q), —CO₂R^(r), —CONR^(r)R^(s), —C(O)R^(r),    —OC(O)NR^(r)R^(s), —NR^(r)C(O)R^(s), —NR^(r)C(O)₂R^(q),    —NR^(r)—C(O)NR^(r)R^(s), —NR^(r)R^(s), —OR^(r), —O—X⁵—OR^(r),    —O—X⁵—NR^(r)R^(s), —O—X⁵—CO₂R^(r), —O—X⁵—CONR^(r)R^(s), —X⁵—OR^(r),    —X⁵—NR^(r)R^(s), —X⁵—CO₂R^(r), —X⁵—CONR^(r)R^(s), —SF₅,    —S(O)₂NR^(r)R^(s), wherein each X⁵ is a C₁₋₄ alkylene; each R^(r)    and R^(s) is independently selected from hydrogen, C₁₋₈ alkyl, and    C₁₋₈ haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O or S, and optionally substituted with oxo; each R^(q) is    independently selected from the group consisting of C₁₋₈ alkyl, and    C₁₋₈ haloalkyl;-   R^(6a) and R^(6c) are each independently selected from the group    consisting of H, C₁₋₄ alkyl and C₁₋₄ haloalkyl;-   m is 0, 1, 2, 3 or 4;-   each R^(6b) is independently selected from the group consisting of    F, C₁₋₄ alkyl, O—R^(u), C₁₋₄ haloalkyl, NR^(u)R^(v), wherein each    R^(u) and R^(v) is independently selected from hydrogen, C₁₋₈ alkyl,    and C₁₋₈ haloalkyl, or when attached to the same nitrogen atom can    be combined with the nitrogen atom to form a five or six-membered    ring having from 0 to 2 additional heteroatoms as ring members    selected from N, O or S, and optionally substituted with oxo.

R³ and R⁴ are joined by forming a bond between atoms of eachsubstituent. In some embodiments, R³ is NR^(g)R^(h) where R^(h) an aminoacid and R^(h) is linked to R⁴ by the alpha carbon substituent of theamino acid. In some embodiments, R³ is NR^(g)R^(h) where R^(h) is anamino acid and R^(h) is linked to R⁴ by the carboxylic acid substituent.In some embodiments, R⁴ is —O—C₁₋₄ alkyl-C₅₋₁₀ heteroaryl and R⁴ isoptionally substituted with R^(4a), where R^(4a) is —CONR^(n)R^(p),R^(p) is C₁₋₈ alkyl, and R^(p) is linked to R³ by the C₁₋₈ alkyl moiety.

In some embodiments, compounds are provided having Formula (I). In otherembodiments, compounds are provided having Formula (II).

In some embodiments, the present disclosure provides compounds havingFormula (Ia) or (IIa):

or a pharmaceutically acceptable salt thereof; wherein:

-   W is N or C(R⁹);-   X, Y and V are each independently selected from the group consisting    of a bond, O, NH, N(CH₃), C(O), methylene and ethylene, wherein the    methylene and ethylene are optionally substituted with one or two    R^(7a);-   R¹ is selected from the group consisting of C₆₋₁₀ aryl and thienyl,    each of which is optionally substituted with 1 to 5 R^(1a)    substituents;-   each R^(7a) and R^(7b) is independently selected from the group    consisting of H, C₁₋₆ alkyl, CO₂H, —CO₂—(C₁₋₆alkyl) and PO₃H₂,    wherein C₁₋₆ alkyl is optionally substituted with one or two members    selected from halogen, OH, NH₂, CN, and CO₂H;-   each R^(8a) and R^(8b) is independently selected from the group    consisting of H and C₁₋₆ alkyl, optionally substituted with halogen,    OH, NH₂, CN, and CO₂H; and-   R⁹ a member selected from the group consisting of H, halogen, CN,    C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —SO₂(C₁₋₆ alkyl), —C₁₋₆ alkyl-CO₂H, —C₁₋₆    alkyl-CO₂—C₁₋₆ alkyl, —C₁₋₆ alkyl-C(O)NH₂, —C₁₋₆ alkyl-C(O)NHC₁₋₆    alkyl and —C₁₋₆ alkyl-C(O)N(C₁₋₆ alkyl)₂,    and the remaining groups have the meanings provided with reference    to Formula (I) and (II) above.

In some embodiments, compounds are provided having Formula (Ia). Inother embodiments, compounds are provided having Formula (IIa).

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof is a compound of Formula (I), (II), (Ia) or (IIa), wherein themacrocycle formed by joining R³ and R⁴ (or by having X, Y and V as ringmembers) is a 12-membered, a 13-membered, a 14-membered, a 15-membered,a 16-membered, a 17-membered, a 18-membered, a 19-membered, or a20-membered macrocycle.

In some embodiments, compounds of Formula (Ib) or Formula (IIb) areprovided:

or a pharmaceutically acceptable salt thereof; wherein:

-   W is N or C(R⁹);-   X, Y and V are each independently selected from the group consisting    of a bond, O, NH, N(CH₃), C(O), methylene and ethylene, wherein the    methylene and ethylene are optionally substituted with one or two    R^(7a);-   each R^(7a) and R^(7b) is independently selected from the group    consisting of H, C₁₋₆ alkyl, CO₂H, CH₂OH, —CO₂—(C₁₋₆alkyl) and    PO₃H₂, wherein C₁₋₆ alkyl is optionally substituted with one or two    members selected from halogen, OH, NH₂, CN, and CO₂H;-   each R^(8a) and R^(8b) is independently selected from the group    consisting of H and C₁₋₆ alkyl, optionally substituted with halogen,    OH, NH₂, CN, and CO₂H; and-   R⁹ a member selected from the group consisting of H, halogen, CN,    C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —SO₂(C₁₋₆ alkyl), —C₁₋₆ alkyl-CO₂H, —C₁₋₆    alkyl-CO₂—C₁₋₆ alkyl, —C₁₋₆ alkyl-C(O)NH₂, —C₁₋₆ alkyl-C(O)NHC₁₋₆    alkyl and —C₁₋₆ alkyl-C(O)N(C₁₋₆ alkyl)₂,    and the remaining groups have the meanings provided with reference    to Formula (I) and (II) above.

In some embodiments, compounds are provided having Formula (Ib). Inother embodiments, compounds are provided having Formula (IIb).

In some embodiments, compounds of Formula (Ic) or Formula (IIc) areprovided:

or a pharmaceutically acceptable salt thereof; wherein:

-   X⁹ is C₁₋₈ alkylene;-   X, Y and V are each independently selected from the group consisting    of a bond, O, NH, N(CH₃), C(O), methylene and ethylene, wherein the    methylene and ethylene are optionally substituted with one or two    R^(7a);-   each R^(7a) and R^(7b) is independently selected from the group    consisting of H, C₁₋₆ alkyl, CO₂H, CH₂OH, —CO₂—(C₁₋₆alkyl) and    PO₃H₂, wherein C₁₋₆ alkyl is optionally substituted with one or two    members selected from halogen, OH, NH₂, CN, and CO₂H; and    -   each R^(8a) and R^(8b) is independently selected from the group        consisting of H and C₁₋₆ alkyl, optionally substituted with        halogen, OH, NH₂, CN, and CO₂H    -   and the remaining groups have the meanings provided with        reference to Formula (I) and (II) above.

In some embodiments, compounds are provided having Formula (Ic). Inother embodiments, compounds are provided having Formula (IIc).

In some embodiments, compounds of Formula (Ia1) and Formula (IIa1) areprovided:

or a pharmaceutically acceptable salt thereof; wherein:

-   W is N or C(R⁹);-   R¹ is selected from the group consisting of C₆₋₁₀ aryl and thienyl,    each of which is optionally substituted with 1 to 5 R^(1a)    substituents;-   each R^(7a) and R^(7b) is independently selected from the group    consisting of H, C₁₋₆ alkyl, CO₂H, CH₂OH, —CO₂—(C₁₋₆alkyl) and    PO₃H₂, wherein C₁₋₆ alkyl is optionally substituted with one or two    members selected from halogen, OH, NH₂, CN, and CO₂H; and-   R⁹ a member selected from the group consisting of H, halogen, CN,    C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —SO₂(C₁₋₆ alkyl), —C₁₋₆ alkyl-CO₂H, —C₁₋₆    alkyl-CO₂—C₁₋₆ alkyl, —C₁₋₆ alkyl-C(O)NH₂, —C₁₋₆ alkyl-C(O)NHC₁₋₆    alkyl and —C₁₋₆ alkyl-C(O)N(C₁₋₆ alkyl)₂,    and the remaining groups have the meanings provided with reference    to Formula (I) and (II) above.

In some embodiments, compounds are provided having Formula (Ia1). Inother embodiments, compounds are provided having Formula (IIa1).

In some embodiments, compounds of Formula (Ib1) and Formula (IIb1) areprovided:

or a pharmaceutically acceptable salt thereof; wherein:

-   W is N or C(R⁹);-   each R^(7a) and R^(7b) is independently selected from the group    consisting of H, C₁₋₆ alkyl, CO₂H, —CO₂—(C₁₋₆alkyl) and PO₃H₂,    wherein C₁₋₆ alkyl is optionally substituted with one or two members    selected from halogen, OH, NH₂, CN, and CO₂H;-   R⁹ a member selected from the group consisting of H, halogen, CN,    C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —SO₂(C₁₋₆ alkyl), —C₁₋₆ alkyl-CO₂H, —C₁₋₆    alkyl-CO₂—C₁₋₆ alkyl, —C₁₋₆ alkyl-C(O)NH₂, —C₁₋₆ alkyl-C(O)NHC₁₋₆    alkyl and —C₁₋₆ alkyl-C(O)N(C₁₋₆ alkyl)₂,    and the remaining groups have the meanings provided with reference    to Formula (I) and (II) above.

In some embodiments, compounds are provided having Formula (Ib1). Inother embodiments, compounds are provided having Formula (IIb1).

In some embodiments, compounds of Formula (Ic1) and Formula (IIc1) areprovided:

or a pharmaceutically acceptable salt thereof; wherein:

-   W is N or C(R⁹);-   each R^(7a) and R^(7b) is independently selected from the group    consisting of H, C₁₋₆ alkyl, CO₂H, CH₂OH, —CO₂—(C₁₋₆alkyl) and    PO₃H₂, wherein C₁₋₆ alkyl is optionally substituted with one or two    members selected from halogen, OH, NH₂, CN, and CO₂H;    -   R⁹ a member selected from the group consisting of H, halogen,        CN, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —SO₂(C₁₋₆ alkyl), —C₁₋₆        alkyl-CO₂H, —C₁₋₆ alkyl-CO₂—C₁₋₆ alkyl, —C₁₋₆ alkyl-C(O)NH₂,        —C₁₋₆ alkyl-C(O)NHC₁₋₆ alkyl and —C₁₋₆ alkyl-C(O)N(C₁₋₆ alkyl)₂    -   and the remaining groups have the meanings provided with        reference to Formula (I) and (II) above.

In some embodiments, compounds are provided having Formula (Ic1). Inother embodiments, compounds are provided having Formula (IIc1).

In some embodiments for each of Formula (I), (II), (Ia), (IIa), (Ia1)and (IIa1), R¹ is selected from the group consisting of phenyl andthienyl, wherein the phenyl and thienyl are optionally substituted with1 to 5 R^(1a) substituents, and in some embodiments with 1 to 3 R^(1a).In some embodiments, R¹ is phenyl optionally substituted with 1 or 2R^(1a) substituents, wherein each R^(1a) is independently selected fromhalogen, C₁₋₈ alkyl, O—C₁₋₈ alkyl, O—C₁₋₈ haloalkyl, —NR^(a)R^(b), andCN, and optionally when two R^(1a) substituents are on adjacent atoms,they are combined to form a fused six-membered heterocyclic ringoptionally substituted with from 1 to 3 substituents independentlyselected from oxo, C₁₋₈ haloalkyl and C₁₋₈ alkyl. In some embodiments,R¹ is phenyl optionally substituted with F. In some embodiments, R¹ isselected from the group consisting of:

In some embodiments of Formula (I), (II), (Ib), (IIb), (Ib1) (IIb1),(Ic), (IIc), (Ic1), and (IIc1) the group Z-L- is selected from

In some embodiments of Formula (I), (II), (Ib), (IIb), (Ib1), (IIb1),(Ic), (IIc), (Ic1), and (IIc1) the group Z-L- is selected from

In some embodiments of Formula (I), (II), (Ib), (IIb), (Ib1), (IIb1),(Ic), (IIc), (Ic1), and (IIc1) the group Z-L- is selected from

In some embodiments for each of Formula (I), (II), (Ia), (IIa), (Ia1),(IIa1), (Ib), (IIb), (Ib1), (IIb1), (Ic), (IIc), (Ic1), and (IIc1) eachR^(2a), R^(2b) and R^(2c) is independently selected from the groupconsisting of H, halogen, —CN, —R^(d), —NR^(e)R^(f), —OR^(e),—X²—OR^(e), —X²—NR^(e)R^(f), wherein X² is C₁₋₄ alkylene; each R^(e) andR^(f) is independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈haloalkyl, or when attached to the same nitrogen atom can be combinedwith the nitrogen atom to form a five or six-membered ring having from 0to 2 additional heteroatoms as ring members selected from N, O or S, andoptionally substituted with oxo; each R^(d) is independently selectedfrom the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₁₋₈haloalkyl. In some embodiments, R^(2b) and R^(2c) are both H and R^(2a)is selected from the group consisting of halogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₁₋₃ haloalkyl, —CN, —OMe and OEt. In some embodiments, R^(2b)and R^(2c) are both H and R^(2a) is halogen. In some embodiments, R^(2b)and R^(2c) are both H and R^(2a) is Cl.

In some embodiments the compound, or a pharmaceutically acceptable saltthereof is a compound of Formula (I), (II), (Ia), (IIa), (Ia1), (IIa1),(Ib), (IIb), (Ib1), (IIb1), or (Ic), (IIc), (Ic1), and (IIc1) wherein nis 0, 1 or 2 and each R⁵ is independently selected from the groupconsisting of halogen, —CN, —R^(m), —NR^(n)R^(p), and —OR^(n), whereineach R^(n) and R^(p) is independently selected from hydrogen, C₁₋₈ alkyland C₁₋₈ haloalkyl and each R^(m) is independently selected from thegroup consisting of C₁₋₈ alkyl and C₁₋₈ haloalkyl. In some embodiments,n is 0.

In some embodiments the compound, or a pharmaceutically acceptable saltthereof is a compound of Formula (I), (II), (Ia), (IIa), (Ia1), (IIa1),(Ib), (IIb), (Ib1), (IIb1), (Ic), (IIc), (Ic1), or (IIc1) wherein R^(6a)is H. In some embodiments, m is 0. In some embodiments, m is 1 andR^(6b) is selected from the group consisting of F, C₁₋₄ alkyl, O—R^(q),C₁₋₄ haloalkyl and NR^(q)R^(r), wherein each R^(g) and R^(r) isindependently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl. Insome embodiments, m is 1 and R^(6b) is F.

In some embodiments, R⁹ in compounds having Formula (Ia), (IIa), (Ib),(IIb), (Ia1), (IIa1), (Ib1), (IIb1), (Ic1) and (IIc1) is CN. In someembodiments, W in compounds having Formula (Ia1), (IIa1), (Ib1), (IIb1),(Ic1) or (IIc1) is N.

In some embodiments, each R^(7a) and R^(7b) in compounds having Formula(Ia), (IIa), (Ib), (IIb), (Ic), (IIc), (Ia1), (IIa1), (Ib1), (IIb1),(Ic1) and (IIc1) is independently selected from the group consisting ofH, CO₂H, and CH₂OH.

In some embodiments the compound, or a pharmaceutically acceptable saltthereof is a compound of Formula (I), (Ia), or (Ia1), wherein theportion shown as

is

In some embodiments the compound, or a pharmaceutically acceptable saltthereof is a compound of Formula (I), (Ia), or (Ia1), wherein theportion shown as

In some embodiments the compound, or a pharmaceutically acceptable saltthereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or(Ic1), wherein the portion shown as

is

Returning to each of Formula (I), (II), (Ia), (IIa), (Ia1), (IIa1),(Ib), (IIb), (Ib1) (IIb1), (Ic), (IIc), (Ic1), and (IIc1) in someembodiments, R⁴ is optionally substituted with 1 to 2 R^(4a), whereineach R^(4a) is independently selected from the group consisting ofhalogen, —CN, —R^(i), —CO₂R^(j), —CONR^(j)R^(k), —C(O)R^(j),—OC(O)NR^(j)R^(k), —NR^(j)C(O)R^(k), —NR^(j)C(O)₂R^(i),—NR^(j)—C(O)NR^(j)R^(k), —NR^(j)R^(k), —OR^(j), and —S(O)₂NR^(j)R^(k).In some embodiments, R⁴ is selected from the group consisting of O—C₁₋₄alkyl, O—C₁₋₆ alkyl-CN, phenyl, pyridinyl, —O—C₁₋₂ alkyl-pyridinyl,—O—C₁₋₂ alkyl-pyrimidinyl, —O—C₁₋₂ alkyl-pyridazinyl, and —O—C₁₋₂alkyl-phenyl, each of which is optionally substituted with 1 to 2R^(4a), wherein each R^(4a) is independently selected from the groupconsisting of halogen, —CN, —CO₂R^(j), —NR^(j)R^(k), and —OR^(j).

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, is selected from the compounds of Table 1 having an activity of++ or +++. In some embodiments, the compound, or a pharmaceuticallyacceptable salt thereof, is selected from the compounds of Table 1having an activity of +++. In some embodiments, the compound, or apharmaceutically acceptable salt thereof, is selected from the compoundsof Table 1 having an activity of ++. In some embodiments, the compound,or a pharmaceutically acceptable salt thereof, is selected from thecompounds of Table 1 having an activity of +.

In addition to the compounds provided above, pharmaceutically acceptablesalts of those compounds are also provided. In some embodiments, thepharmaceutically acceptable salts are selected from ammonium, calcium,magnesium, potassium, sodium, zinc, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, hydrochloric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, acetic, propionic,isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, arginate, glucuronic acid and galactunoric acids. Insome embodiments, the pharmaceutically acceptable salts are selectedfrom ammonium, calcium, magnesium, potassium, sodium, hydrochloric,carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, acetic, propionic, isobutyric, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, arginate, glucuronicacid and galactunoric acids. In some embodiments, the pharmaceuticallyacceptable salts are sodium or hydrochloric.

In addition to salt forms, the present disclosure provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentdisclosure. Additionally, prodrugs can be converted to the compounds ofthe present disclosure by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present disclosure when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

An ester may be used as a prodrug for the corresponding carboxylic acid.A C₁₋₁₀ alkyl ester or a C₁₋₁₀ haloalkyl ester may be used as a prodrugfor the corresponding carboxylic acid. The following esters may be used:ter-butyl ester, methyl ester, ethyl ester, isopropyl ester. Morespecifically, ester prodrugs may be used as R³ groups such as threonineor serine prodrug esters which are linked to the rest of the moleculethrough their nitrogen. More specifically, the following prodrugs may beused for R³:

More specifically, the following prodrugs may be used for R³:

Pharmaceutical Compositions

In addition to the compounds provided herein, compositions of thosecompounds will typically contain a pharmaceutical carrier or diluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In another embodiment, a pharmaceutical composition comprising acompound of the present disclosure including a compound of Formula (I),(Ia), (II), or (IIa) or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable excipient, is provided.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutic agents. In some embodiments, the oneor more additional therapeutic agent is selected from the groupconsisting of an antimicrobial agent, an antiviral agent, a cytotoxicagent, a gene expression modulatory agent, a chemotherapeutic agent, ananti-cancer agent, an anti-angiogenic agent, an immunotherapeutic agent,an anti-hormonal agent, an anti-fibrotic agent, radiotherapy, aradiotherapeutic agent, an anti-neoplastic agent, and ananti-proliferation agent. In some embodiments, the one or moreadditional therapeutic agent is selected from the group consisting ofone or more of CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239,CCX9664, CCX2553, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765,CCX224, CCX662, CCX650, CCX832, CCX168, and CCX168-M1.

The pharmaceutical compositions for the administration of the compoundsof this disclosure may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacyand drug delivery. All methods include the step of bringing the activeingredient into association with the carrier which constitutes one ormore accessory ingredients. In general, the pharmaceutical compositionsare prepared by uniformly and intimately bringing the active ingredientinto association with a liquid carrier or a finely divided solid carrieror both, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self-emulsifications as described in U.S. PatentApplication 2002-0012680, hard or soft capsules, syrups, elixirs,solutions, buccal patch, oral gel, chewing gum, chewable tablets,effervescent powder and effervescent tablets. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents, antioxidants andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as cellulose, silicon dioxide, aluminumoxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example PVP, cellulose, PEG, starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated,enterically or otherwise, by known techniques to delay disintegrationand absorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate may beemployed. They may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and U.S. Pat. No. 4,265,874 to formosmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, polyethyleneglycol (PEG) of various average sizes (e.g., PEG400, PEG4000) andcertain surfactants such as cremophor or solutol, or as soft gelatincapsules wherein the active ingredient is mixed with water or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such as mono- ordi-glycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the disclosure may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present disclosure may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols. Additionally, the compounds can be administeredvia ocular delivery by means of solutions or ointments. Still further,transdermal delivery of the subject compounds can be accomplished bymeans of iontophoretic patches and the like. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present disclosure are employed. As used herein,topical application is also meant to include the use of mouth washes andgargles.

The compounds of this disclosure may also be coupled to a carrier thatis a suitable polymer as a targetable drug carrier. Such polymers caninclude polyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylami de-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thedisclosure may be coupled to a carrier that is a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like. In one embodiment ofthe disclosure, the compound of the disclosure is coupled to a polymeror semipermeable polymer matrix that is formed as a stent or stent-graftdevice.

Methods of Treating Diseases and Disorders

The compounds of the disclosure may be used as immunomodulators. Thecompounds of the disclosure may be used as agonists, antagonists,partial agonists, inverse agonists, inhibitors of PD-1 and/or PD-L1 in avariety of contexts, both in vitro and in vivo. In some embodiments, thecompounds of the disclosure may be used as inhibitors of the PD-1/PD-L1protein protein interaction. In some embodiments, the compounds of thedisclosure may be used as inhibitors of PD-L1. In some embodiments, thecompounds of the disclosure may be used as inhibitors of the CD80/PD-L1protein protein interaction. In some embodiments, the compounds of thedisclosure may be used to inhibit the interaction between PD-1 and PD-L1and/or PD-1 and CD80 and/or PD-1 and PD-L2 in vitro or in vivo. In someembodiments, the compounds of the disclosure may be used to inhibitVISTA and/or TIM-3. In some embodiments, the compounds of the disclosuremay be inhibitors of the PD-1/PD-L1 protein protein interaction andinhibitors of VISTA and/or TIM-3. In some embodiments, in addition tobeing inhibitors of the PD-1/PD-L1 protein protein interaction, thecompounds of the disclosure may be inhibitors of CTLA-4 and/or BTLAand/or LAG-3 and/or KLRG-1 and/or 2B4 and/or CD160 and/or HVEM and/orCD48 and/or E-cadherin and/or MHC-II and/or galectin-9 and/or CD86and/or PD-L2 and/or VISTA and/or TIM-3 and/or CD80.

The compounds of the disclosure may be contacted with the receptor theyinteract with, in aqueous solution and under conditions otherwisesuitable for binding of the ligand to the receptor. The receptor may bepresent in suspension (e.g., in an isolated membrane or cellpreparation), in a cultured or isolated cell, or in a tissue or organ.

Preferably, the amount of the compounds of the disclosure contacted withthe receptor should be sufficient to inhibit the PD-1/PD-L1 binding invitro as measured, for example, using an ELISA. The receptor may bepresent in solution or suspension, in a cultured or isolated cellpreparation or within a patient.

In some embodiments, the compounds of the present disclosure are usefulfor restoring and augmenting T cell activation. In some embodiments, thecompounds of the present disclosure are useful for enhancing an immuneresponse in a patient. In some embodiments, the compounds of the presentdisclosure are useful for treating, preventing, or slowing theprogression of diseases or disorders in a variety of therapeutic areas,such as cancer and infectious diseases.

In some embodiments, the compounds of the present disclosure can be usedfor treating patients suffering from conditions that are responsive toPD-1/PD-L1 protein protein interaction modulation.

In some embodiments, a method of modulating an immune response mediatedby the PD-1 signaling pathway in a subject, comprising administering tothe subject a therapeutically effective amount of a compound of thepresent disclosure including a compound of Formula (I), (Ia), (II), or(IIa) or a pharmaceutically acceptable salt thereof or a compositioncomprising a compound of the present disclosure including a compound ofFormula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable saltthereof, is provided.

In some embodiments, a method of enhancing, stimulating, modulatingand/or increasing the immune response in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present disclosure including a compound ofFormula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable saltthereof or a composition of a compound of the present disclosureincluding a compound of Formula (I), (Ia), (II), or (IIa), or apharmaceutically acceptable salt thereof, is provided.

In some embodiments, a method of inhibiting growth, proliferation, ormetastasis of cancer cells in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of the present disclosure including a compound of Formula (I),(Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof or acomposition of a compound of the present disclosure including a compoundof Formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptablesalt thereof, is provided.

In some embodiments, a method of treating a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present disclosure including a compound ofFormula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable saltthereof or a composition of a compound of the present disclosureincluding a compound of Formula (I), (Ia), (II), or (IIa), or apharmaceutically acceptable salt thereof, is provided.

In some embodiments, the subject suffers from a disease or disorderselected from the group consisting of an infectious disease, a bacterialinfectious disease, a viral infectious disease a fungal infectiousdisease, a solid tumor, a hematological malignancy, an immune disorder,an inflammatory disease, and cancer. In some embodiments, the disease ordisorder is selected from the group consisting of melanoma,glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma,lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma,diffuse large B-cell lymphoma, primary mediastinal large B-celllymphoma, prostate cancer, castration-resistant prostate cancer, chronicmyelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma,synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of softtissue, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymusneoplasm, cancer of the thyroid gland, cancer of the parathyroid gland,uterine cancer, cancer of the adrenal gland, liver infection, Merkelcell carcinoma, nerve tumor, follicle center lymphoma, colon cancer,Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acuteleukemias including acute myeloid leukemia, chronic myeloid leukemia,acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiplemyeloma, ovary tumor, myelodysplastic syndrome, cutaneous or intraocularmalignant melanoma, renal cell carcinoma, small-cell lung cancer, lungcancer, mesothelioma, breast cancer, squamous non-small cell lung cancer(SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastriccancer, hepatocellular carcinoma, pancreatic carcinoma, pancreaticcancer, Pancreatic ductal adenocarcinoma, squamous cell carcinoma of thehead and neck, cancer of the head or neck, gastrointestinal tract,stomach cancer, HIV, Hepatitis A, Hepatitis B, Hepatitis C, hepatitis D,herpes viruses, papillomaviruses, influenza, bone cancer, skin cancer,rectal cancer, cancer of the anal region, testicular cancer, carcinomaof the fallopian tubes, carcinoma of the endometrium, carcinoma of thecervix, carcinoma of the vagina, carcinoma of the vulva, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the urethra, cancer of the penis, cancer of thebladder, cancer of the kidney, cancer of the ureter, carcinoma of therenal pelvis, neoplasm of the central nervous system (CNS), tumorangiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma,epidermoid cancer, abestosis, carcinoma, adenocarcinoma, papillarycarcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cellcarcinoma, transitional cell carcinoma, choriocarcinoma, seminoma,embryonal carcinoma, wilm's tumor, pleomorphic adenoma, liver cellpapilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma,leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma,lipoma and fibroma.

In some embodiments, a therapeutically effective amount of one or moreadditional therapeutic agents is further administered to the subject. Insome embodiments, the one or more additional therapeutic agents isselected from the group consisting of an antimicrobial agent, anantiviral agent, a cytotoxic agent, a gene expression modulatory agent,a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenicagent, an immunotherapeutic agent, an anti-hormonal agent, ananti-fibrotic agent, radiotherapy, a radiotherapeutic agent, ananti-neoplastic agent, and an anti-proliferation agent. In someembodiments, the one or more additional therapeutic agent is selectedfrom the group consisting of one or more of CCX354, CCX9588, CCX140,CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX 2991, CCX282, CCX025,CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, andCCX168-M1.

In some embodiments, the compounds of the present disclosure may be usedto inhibit an infectious disease. The infectious disease includes but isnot limited to HIV, Influenza, Herpes, Giardia, Malaria, Leishmania, thepathogenic infection by the virus Hepatitis (A, B, and C), herpes virus(e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein Barr virus),adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus,coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus,rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus,HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus,rabies virus, JC virus and arboviral encephalitis virus, pathogenicinfection by the bacteria chlamydia, rickettsial bacteria, mycobacteria,staphylococci, streptococci, pneumonococci, meningococci and conococci,klebsiella, proteus, serratia, pseudomonas, E. coli, legionella,diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax,plague, leptospirosis, and Lyme's disease bacteria, pathogenic infectionby the fungi Candida (albicans, krusei, glabrata, tropicalis, etc.),Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), GenusMucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomycesdermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis andHistoplasma capsulatum, and pathogenic infection by the parasitesEntamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoebasp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii,Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosomacruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylusbrasiliensis.

In some embodiments, the compounds of the present disclosure may be usedto inhibit HIV infection, delay AIDS progression, deplete HIV viralreservoir or decrease the severity of symptoms or HIV infection andAIDS.

The compounds of the present disclosure may be used for the treatment ofcancers and precancerous conditions in a subject.

Treatment methods provided herein include, in general, administration toa patient an effective amount of one or more compounds provided herein.Suitable patients include those patients suffering from or susceptibleto (i.e., prophylactic treatment) a disorder or disease identifiedherein. Typical patients for treatment as described herein includemammals, particularly primates, especially humans. Other suitablepatients include domesticated companion animals such as a dog, cat,horse, and the like, or a livestock animal such as cattle, pig, sheepand the like.

In general, treatment methods provided herein comprise administering toa patient an effective amount of a compound one or more compoundsprovided herein. In a preferred embodiment, the compound(s) of thedisclosure are preferably administered to a patient (e.g., a human)intravenously, orally or topically. The effective amount may be anamount sufficient to modulate the PD-1/PD-L1 interaction and/or anamount sufficient to reduce or alleviate the symptoms presented by thepatient. Preferably, the amount administered is sufficient to yield aplasma concentration of the compound (or its active metabolite, if thecompound is a pro-drug) high enough to sufficient to modulate thePD-1/PD-L1 interaction. Treatment regimens may vary depending on thecompound used and the particular condition to be treated; for treatmentof most disorders, a frequency of administration of 4 times daily orless is preferred. In general, a dosage regimen of 2 times daily is morepreferred, with once a day dosing particularly preferred. It will beunderstood, however, that the specific dose level and treatment regimenfor any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination (i.e., other drugsbeing administered to the patient) and the severity of the particulardisease undergoing therapy, as well as the judgment of the prescribingmedical practitioner. In general, the use of the minimum dose sufficientto provide effective therapy is preferred. Patients may generally bemonitored for therapeutic effectiveness using medical or veterinarycriteria suitable for the condition being treated or prevented.

Combinations

A concomitant medicine comprising the compounds of the presentdisclosure and other drug may be administered as a combinationpreparation in which both components are contained in a singleformulation, or administered as separate formulations. Theadministration by separate formulations includes simultaneousadministration and administration with some time intervals. In the caseof the administration with some time intervals, the compound of thepresent disclosure can be administered first, followed by another drugor another drug can be administered first, followed by the compound ofthe present disclosure. The administration method of the respectivedrugs may be the same or different.

The dosage of the other drug can be properly selected, based on a dosagethat has been clinically used. The compounding ratio of the compound ofthe present disclosure and the other drug can be properly selectedaccording to age and weight of a subject to be administered,administration method, administration time, disorder to be treated,symptom and combination thereof. For example, the other drug may be usedin an amount of 0.01 to 100 parts by mass, based on 1 part by mass ofthe compound of the present disclosure. The other drug may be acombination of two or more kind of arbitrary drugs in a properproportion.

The compounds described herein may be used or combined with one or moretherapeutic agent such as an antimicrobial agent, an antiviral agent, acytotoxic agent, a gene expression modulatory agent, a chemotherapeuticagent, an anti-cancer agent, an anti-angiogenic agent, animmunotherapeutic agent, an anti-hormonal agent, an anti-fibrotic agent,radiotherapy, a radiotherapeutic agent, an anti-neoplastic agent, and ananti-proliferation agent. These therapeutic agents may be in the formsof compounds, antibodies, polypeptides, or polynucleotides.

The compounds described herein may be used or combined with one or moreof a therapeutic antibody, a bispecific antibody and “antibody-like”therapeutic protein (such as DARTs®, Duobodies®, Bites®, XmAbs®,TandAbs®, Fab derivatives), an antibody-drug conjugate (ADC), a virus,an oncolytic virus, gene modifiers or editors such as CRISPR (includingCRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), aCAR (chimeric antigen receptor) T-cell immunotherapeutic agent, or anycombination thereof.

Examples of chemotherapeutics include an alkylation agent, nitrosoureaagent, antimetabolite, anticancer antibiotics, vegetable-originalkaloid, topoisomerase inhibitor, hormone drug, hormone antagonist,aromatase inhibitor, P-glycoprotein inhibitor, platinum complexderivative, other immunotherapeutic drugs and other anticancer drugs.

The compounds described herein may be used or combined with a cancertreatment adjunct, such as a leucopenia (neutropenia) treatment drug,thrombocytopenia treatment drug, antiemetic and cancer pain interventiondrug, concomitantly or in a mixture form.

The compounds described herein may be used or combined with a kinaseinhibitor.

In one embodiment, the compounds of the present disclosure can be usedwith other immunomodulators and/or a potentiating agent concomitantly orin a mixture form. Examples of the immunomodulator include variouscytokines, vaccines and adjuvants. Examples of these cytokines, vaccinesand adjuvants that stimulates immune responses include but not limitedto GM-CSF, M-CSF, G-CSF, interferon-a, beta, or gamma, IL-1, IL-2, IL-3,IL-12, Poly (I:C) and CPG. The potentiating agents includecyclophosphamide and analogs of cyclophosphamide, anti-TGF and imatinib(Gleevac), a mitosis inhibitor, such as paclitaxel, Sunitinib (Sutent)or other antiangiogenic agents, an aromatase inhibitor, such asletrozole, an A2a adenosine receptor (A2AR) antagonist, an angiogenesisinhibitor, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists,and IL-18 antagonists.

In some embodiments, the compounds described herein may be used orcombined with one or more modulator of CCR1, CCR2, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5,CXCR6, CXCR7, CX₃CR1, ChemR23, C5aR, C5a, and C5. In some embodiments,the modulator is an antagonist.

In some embodiments, the compounds described herein may be used orcombined with one or more of CCX354, CCX9588, CCX140, CCX872, CCX598,CCX6239, CCX9664, CCX2553, CCX 2991, CCX282, CCX025, CCX507, CCX430,CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, and CCX168-M1.

Dosage

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment orpreventions of conditions involving the PD-1/PD-L1 interaction (about0.5 mg to about 7 g per human patient per day). The amount of activeingredient that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration. Dosage unit forms will generallycontain between from about 1 mg to about 500 mg of an active ingredient.For compounds administered orally, transdermally, intravaneously, orsubcutaneously, it is preferred that sufficient amount of the compoundbe administered to achieve a serum concentration of 5 ng(nanograms)/mL-10 μg (micrograms)/mL serum, more preferably sufficientcompound to achieve a serum concentration of 20 ng-1 μg/ml serum shouldbe administered, most preferably sufficient compound to achieve a serumconcentration of 50 ng/ml-200 ng/ml serum should be administered. Fordirect injection into the synovium (for the treatment of arthritis)sufficient compounds should be administered to achieve a localconcentration of approximately 1 micromolar.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily, three times daily, or less ispreferred, with a dosage regimen of once daily or 2 times daily beingparticularly preferred. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, and rate of excretion, drugcombination (i.e., other drugs being administered to the patient), theseverity of the particular disease undergoing therapy, and otherfactors, including the judgment of the prescribing medical practitioner.

In another aspect of the disclosure, the compounds of the disclosure canbe used in a variety of non-pharmaceutical in vitro and in vivoapplication. The compounds of the disclosure may also be used aspositive controls in assays for PD-1/PD-L1 interaction activity, i.e.,as standards for determining the ability of a candidate agent to bind toPD-1 and/or PD-L1, or as radiotracers for positron emission tomography(PET) imaging or for single photon emission computerized tomography(SPECT).

Also within the scope of the present disclosure are kits comprising acompound of the present disclosure or pharmaceutically acceptable saltsthereof and instructions for use. The kit can further contain at leastone additional reagent. Kits typically include a label indicating theintended use of the contents of the kit. The term label includes anywriting, or recorded material supplied on or with the kit, or whichotherwise accompanies the kit.

General Synthetic Procedures

The embodiments are also directed to processes and intermediates usefulfor preparing the subject compounds or pharmaceutically acceptable saltsthereof.

Exemplary chemical entities useful in methods of the embodiments willnow be described by reference to illustrative synthetic schemes fortheir general preparation herein and in the specific examples thatfollow. Artisans will recognize that, to obtain the various compoundsherein, starting materials may be suitably selected so that theultimately desired substituents will be carried through the reactionscheme with or without protection as appropriate to yield the desiredproduct. Alternatively, it may be necessary or desirable to employ, inthe place of the ultimately desired substituent, a suitable group thatmay be carried through the reaction scheme and replaced as appropriatewith the desired substituent. Furthermore, one of skill in the art willrecognize that the transformations shown in the schemes below may beperformed in any order that is compatible with the functionality of theparticular pendant groups.

Representative syntheses of compounds of the present disclosure aredescribed in the scheme below, and the particular examples that follow.Schemes 1 and 2 are provided as further embodiment of the disclosure andillustrate general methods which were used to prepare compounds of thepresent disclosure including compounds of Formula (I), (Ia), (II), or(IIa), and which can be used to prepare additional compounds having theFormula (I), (Ia), (II), or (IIa). The methodology is compatible with awide variety of functionalities.

The 3-bromobenzyl alcohol can be subjected to Suzuki coupling conditionsto introduce the appropriate R¹ group. In the subsequent step, the etherbond can be formed using reagents such as triphenyl phosphine anddiisopropyl or diethyl azodicarboxylate. Alkylation of the phenolintermediate can be achieved using the appropriate alkyl halide ormesylate reagent. Carboxylic acid methyl ester hydrolysis can beachieved using a base such lithium hydroxide. The reductive aminationcan be accomplished using the appropriate amine and a reducing agentsuch as sodium triacetoxyborohydride in the presence of mild acid suchas acetic acid. Boc deprotection can be achieved using HCl. Themacrolactam formation can be achieved using EDAC and HOBt under dilutereaction conditions. And the carboxylic acid methyl ester hydrolysis canbe achieved using a base such as lithium hydroxide. The transformationsshown in Scheme 1 may be performed in any order that is compatible withthe functionality of the particular pendant groups.

The 4-bromoindanol derivative can be subjected to Suzuki couplingconditions to introduce the appropriate R¹ group. In the subsequentstep, the ether bond can be formed using reagents such as triphenylphosphine and diisopropyl or diethyl azodicarboxylate. Alkylation of thephenol intermediate can be achieved using the appropriate alkyl halideor mesylate reagent. Carboxylic acid methyl ester hydrolysis can beachieved using a base such lithium hydroxide. The reductive aminationcan be accomplished using the appropriate amine and a reducing agentsuch as sodium triacetoxyborohydride in the presence of mild acid suchas acetic acid. Boc deprotection can be achieved using HCl. Themacrolactam formation can be achieved using EDAC and HOBt under dilutereaction conditions. And the carboxylic acid methyl ester hydrolysis canbe achieved using a base such as lithium hydroxide. The transformationsshown in Scheme 2 may be performed in any order that is compatible withthe functionality of the particular pendant groups and using opticallypure (R)-4-bromoindanol or (S)-4-bromoindanol.

As an example, enrichment of optical purity of chiral intermediates canbe achieved as described in Scheme 3.

EXAMPLES

The following Examples illustrate various methods of making compounds ofthis disclosure including compounds of Formula (I), (Ia), (II), or(IIa). The following examples are offered to illustrate, but not tolimit the claimed disclosure.

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR spectra wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare provided relative to TMS and are tabulated in the order:multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet) and number of protons. Mass spectrometry results are reportedas the ratio of mass over charge. In the examples, a single m/z value isreported for the M+H (or, as noted, M−H) ion containing the most commonatomic isotopes. Isotope patterns correspond to the expected formula inall cases. Electrospray ionization (ESI) mass spectrometry analysis wasconducted on a Hewlett-Packard MSD electrospray mass spectrometer usingthe HP1100 HPLC for sample delivery. Normally the analyte was dissolvedin methanol or CH₃CN at 0.1 mg/mL and 1 microliter was infused with thedelivery solvent into the mass spectrometer, which scanned from 100 to1000 Daltons. All compounds could be analyzed in the positive ornegative ESI mode, using acetonitrile/water with 1% formic acid as thedelivery solvent.

The following abbreviations are used in the Examples and throughout thedescription of the disclosure: TLC means Thin layer chromatography, DMFmeans dimethylformamide, EDAC meansN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, DIPEAmeans N,N-diisopropylethylamine, HOBT means 1-hydroxybenzotriazolehydrate, DCM means dichloromethane, THF means tetrahydrofuran, PBS meansphosphate buffered saline, BSA means bovine serum albumin, HRP meanshorseradish peroxidase, and TMB means 3,3′,5,5′ tetramethyl benzidine.

Compounds within the scope of this disclosure can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. One skilled in the art will also recognize that alternativemethods may be employed to synthesize the target compounds of thisdisclosure, and that the approaches described within the body of thisdocument are not exhaustive, but do provide broadly applicable andpractical routes to compounds of interest.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are claimed unless a specific enantiomer is specified.

The detailed description of the experimental procedures used tosynthesize key compounds in this text lead to molecules that aredescribed by the physical data identifying them as well as by thestructural depictions associated with them.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Example 1: Synthesis of the lithium salt of(S)-4⁴-chloro-5⁴-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-13-oxo-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphane-7-carboxylicacid

Step a:

To a 100 mL round bottom flask was added 5-chloro-2hydroxy-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxybenzaldehyde (1.0 g,2.8 mmol), methyl-5-(chloromethy)nicotinate hydrochloride salt (0.82 g,3.7 mmol), cesium carbonate (4.6 g, 14.5 mmol), sodium iodide (42 mg,0.28 mmol), and DMF (20 mL). The mixture was stirred at room temperaturefor 2 days. Water (50 mL) was added and the aqueous mixture wasextracted with EtOAc (3×50 mL). The organics were combined, dried overMgSO₄, filtered, and concentrated in vacuo to afford methyl5-((4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinate.

Step b:

To a biphasic solution of methyl5-((4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinate(470 mg, 0.93 mmol) in dioxane (5.0 mL) and water (0.5 mL) was addedlithium hydroxide monohydrate (40 mg, 0.93 mmol). The mixture wasstirred for 2 hours at room temperature and then concentrated in vacuoto afford5-((4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid.

Step c:

To a solution of5-((4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid (230 mg, 0.47 mmol) and N′-Fmoc-L-lysine methyl ester hydrochloride(0.97 g, 2.33 mmol) in DMF (6 mL) was added acetic acid (133 μL, 2.33mmol) and N,N-diisopropylethylamine (283 μL, 1.63 mmol). The mixture wasallowed to stir at room temperature for 15 min before sodiumtriacetoxyborohydride (300 mg, 1.40 mmol) was added in portions over 5min. After stirring for 1 h, an additional amount of sodiumtriacetoxyborohydride (230 mg, 1.08 mmol) was added in one portion. Thereaction mixture was stirred at room temperature for an additional 4 hbefore the mixture was concentrated in vacuo and purified by flashchromatography (10% MeOH/DCM) to afford(S)-5-((2-(((6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid.

Step d:

To a solution of(S)-5-((2-(((6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid (46 mg, 0.054 mmol) in DMF (0.45 mL) was added piperidine (50 μL).After stirring for 15 min at room temperature, the mixture wasconcentrated in vacuo to afford(S)-5-((2-(((6-amino-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid.

Step e:

To a solutionof(S)-5-((2-(((6-amino-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid (34 mg, 0.054 mmol) in DMF (5.4 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (41 mg,0.22 mmol), 1-hydroxybenzotriazole hydrate (17 mg, 0.11 mmol), andN,N-diisopropylethylamine (94 μL, 0.54 mmol). The mixture was left tostir for 36 h and then concentrated in vacuo. The crude solid wasre-suspended in acetonitrile, filtered, and washed with acetonitrile toafford methyl(S)-4⁴-chloro-4⁵-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-13-oxo-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphane-7-carboxylate.

Step f:

To a biphasic solution of methyl(S)-4⁴-chloro-4⁵-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-13-oxo-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphane-7-carboxylate(13 mg, 0.021 mmol) in dioxane (1 mL) and water (0.5 mL) was addedlithium hydroxide monohydrate (4 mg, 0.064 mmol). After stirring at roomtemperature for 5 h, the reaction mixture was frozen and lyophilized toafford the lithium salt of(S)-4⁴-chloro-5⁴-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-13-oxo-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphane-7-carboxylicacid. MS: (ES) m/z calculated for C₃₄H₃₄ClN₃O₅ [M+H]⁺ 600.2, found600.1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (br s, 1H), 8.81 (s, 1H), 8.79(d, J=2.0 Hz, 1H), 8.74 (s, 1H), 7.50-7.46 (m, 2H), 7.45 (d, J=7.6 Hz,1H), 7.41-7.35 (m, 1H), 7.35-7.30 (m, 2H), 7.26 (d, J=5.8 Hz, 2H), 7.20(d, J=7.5 Hz, 1H), 7.08 (s, 1H), 5.43 (q, J=13.7 Hz, 2H), 5.22 (s, 2H),3.63-3.56 (m, 1H), 3.51-3.44 (m, 1H), 2.71-2.61 (m, 1H), 2.23 (s, 3H),2.00-1.89 (m, 1H), 1.60-1.49 (m, 3H), 1.49-1.35 (m, 4H).

Example 2: Synthesis of the trifluoroacetic acid salt of(S)-4⁴-chloro-4⁵-((3′-(3-(4-hydroxypiperidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-13-oxo-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphane-7-carboxylicacid

Step a:

A mixture of5-chloro-4-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde(100 mg, 0.218 mmol), methyl-5-(chloromethy)nicotinate hydrochloridesalt (48 g, 0.218 mmol), and cesium carbonate (214 g, 0.655 mmol) in DMF(1 mL) was stirred at 70° C. for 2 h. Water (10 mL) was added and theaqueous mixture was extracted with EtOAc (3×20 mL). The organics werecombined, dried over MgSO₄, filtered, and concentrated in vacuo toafford methyl5-((4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinate.

Step b:

To a biphasic solution of methyl5-((4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinate(110 mg, 0.181 mmol) in THF (2 mL) and water (0.228 mL) was added 1Maqueous lithium hydroxide monohydrate (0.272 mL, 0.272 mmol). Themixture was stirred for an hour at room temperature and thenconcentrated in vacuo to afford methyl5-((4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinatelithium salt.

Step c:

To a solution of5-((4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinatelithium salt (110 mg, 0.185 mmol) and methylN⁶-(tert-butoxycarbonyl)-L-lysinate hydrochloride (55 mg, 0.185 mmol) inDMF (2 mL) was added acetic acid (60 μL, 0.925 mmol),N,N-diisopropylethylamine (50 μL, 0.277 mmol) and sodiumtriacetoxyborohydride (78 mg, 0.37 mmol). After stirring for 5 h at roomtemperature, additional sodium triacetoxyborohydride (100 mg, 0.47 mmol)and acetic acid (50 μL, 0.83 mmol) were added and the reaction wasstirred overnight at room temperature. The reaction mixture was dilutedwith 2:1 CHCl₃/isopropanol (30 mL), washed with aqueous 1N HCl (10 mL)and saturated aqueous NaHCO₃ (10 mL), dried (Na₂SO₄), and concentratedin vacuo to afford(S)-5-((2-(((6-((tert-butoxycarbonyl)amino)-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid.

Step d:

To a solution of(S)-5-((2-(((6-((tert-butoxycarbonyl)amino)-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid (162 mg, 0.193 mmol) in dioxane (3 mL) was added 1N HCl in dioxane(1 mL). After stirring for 2 h at room temperature, the mixture wasconcentrated in vacuo to afford(S)-5-((2-(((6-amino-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid hydrochloride.

Step e:

To a solution of(S)-5-((2-(((6-amino-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid hydrochloride (160 mg, 0.189 mmol) in DMF (20 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (300 mg,1.562 mmol), 1-hydroxybenzotriazole hydrate (100 mg, 0.65 mmol), andN,N-diisopropylethylamine (329 μL, 1.89 mmol). The mixture was left tostir overnight at room temperature and then concentrated in vacuo. EtOAc(20 mL) was added to the residue and washed with saturated aqueous NH₄Cl(20 mL). The organic layer was separated and washed with water (10 mL)and brine (10 mL), dried (Na₂SO₄), and concentrated in vacuo. The crudeproduct was purified by automated flash chromatography (SiO₂, 10% MeOHin CH₂Cl₂) to afford methyl(S)-4⁴-chloro-45-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-13-oxo-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphane-7-carboxylate.

Step f:

To a biphasic solution of methyl(S)-4⁴-chloro-45-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-13-oxo-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphane-7-carboxylate(150 mg, 0.209 mmol) in THF (4 mL) and water (0.5 mL) was added 1Maqueous lithium hydroxide (500 μL, 0.5 mmol). After stirring at roomtemperature for 4 h, the reaction mixture was concentrated in vacuo toafford lithium(S)-4⁴-chloro-4⁵-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-13-oxo-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphane-7-carboxylate.

Step g:

To a solution of(S)-4⁴-chloro-4⁵-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-13-oxo-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphane-7-carboxylicacid lithium salt (130 mg, 0.18 mmol) in DMF (3 mL) was addedpiperidin-4-ol (183 mg, 1.8 mmol), K₂CO₃ (124 mg, 0.9 mmol) and NaI (54mg, 0.36 mmol). The resulting suspension was stirred at 80° C.overnight. The reaction mixture was filtered and concentrated in vacuo,and the crude was purified by reverse phase preparative HPLC (CH₃CN—H₂Owith 0.1% TFA) to obtain the trifluoroacetic acid salt of(S)-4⁴-chloro-4⁵-((3′-(3-(4-hydroxypiperidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-13-oxo-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphane-7-carboxylicacid. MS: (ES) m/z calculated for C₄₃H₅₂ClN₄O₇ [M+H]⁺ 771.3, found771.2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.85 (d, J=2.1 Hz, 1H), 8.76-8.71(m, 1H), 8.48 (s, 1H), 7.61 (s, 1H), 7.52 (d, J=7.7 Hz, 1H), 7.24 (dt,J=20.8, 7.9 Hz, 2H), 7.16-7.04 (m, 2H), 6.95 (d, J=8.2 Hz, 1H), 6.73 (d,J=7.6 Hz, 1H), 5.39 (d, J=13.2 Hz, 4H), 4.62-4.54 (m, 1H), 4.24 (d,J=12.3 Hz, 1H), 4.20-4.02 (m, 4H), 3.71-3.54 (m, 2H), 3.50-3.26 (m, 5H),3.28-3.15 (m, 2H), 3.11-3.01 (m, 1H), 2.33-2.24 (m, 3H), 2.11 (s, 5H),1.98-1.89 (m, 5H), 1.83-1.67 (m, 6H), 1.31 (t, J=7.3 Hz, 2H).

Example 3: Synthesis of(S)-1⁴-chloro-4⁵-cyano-1⁵-((3′-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-oxo-2-oxa-6,12-diaza-1(1,2),4(1,3)-dibenze(S)-1⁴-chloro-4⁵-cyano-15-((3′-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-oxo-2-oxa-6,12-diaza-1(1,2),4(1,3)-dibenzenacyclotridecaphane-11-carboxylicacid

Step a:

A mixture of5-chloro-4-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde(1.0 g, 2.18 mmol), methyl 3-(bromomethyl)-5-cyanobenzoate (0.63 g, 2.50mmol), and cesium carbonate (1.77 g, 2.50 mmol) in DMF (7 mL) wasstirred at 100° C. for 1.5 h. Water (20 mL) was added and the aqueousmixture was extracted with EtOAc (3×30 mL). The combined organic layerswere dried over MgSO₄, filtered, and concentrated in vacuo. The crudematerial was purified by flash chromatography (SiO₂, 20% EtOAc in hexaneto 100% EtOAc) to afford methyl3-((4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)-5-cyanobenzoate.

Step b:

To a biphasic solution of methyl3-((4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)-5-cyanobenzoate(250 mg, 0.40 mmol) in dioxane (6 mL) and water (1 mL) was added lithiumhydroxide monohydrate (25 mg, 0.60 mmol). The mixture was heated to 45°C. and allowed to stir for 2.5 h before it was frozen and lyophilized toafford lithium3-((4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)-5-cyanobenzoate.The material was used in the subsequent step without purification.

Step c:

To a solution of lithium3-((4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)-5-cyanobenzoate(220 mg, 0.36 mmol) and N′-Boc-L-lysine methyl ester hydrochloride (116mg, 0.39 mmol) in MeOH (4 mL) was added N,N-diisopropylethylamine (100μL, 0.53 mmol) and Ti(Oi-Pr)₄ (160 μL, 0.53 mmol). The mixture wasallowed to stir at room temperature for 16 h before sodium borohydride(54 mg, 1.42 mmol) was added in portions over 5 min. The reactionmixture was stirred for 15 min and then concentrated in vacuo. The crudematerial was purified by flash chromatography (SiO₂, 100% DCM to 20%MeOH in DCM) to afford(S)-3-((2-(((6-((tert-butoxycarbonyl)amino)-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)-5-cyanobenzoicacid.

Step d:

To a solution of(S)-3-((2-(((6-((tert-butoxycarbonyl)amino)-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)-5-cyanobenzoicacid (146 mg, 0.17 mmol) in DCM (3 mL) was added 4 N HCl in dioxane(0.17 mL, 0.68 mmol). The mixture was allowed to stir at rt for 4 hbefore it was concentrated in vacuo to afford(S)-3-((2-(((6-amino-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)-5-cyanobenzoicacid hydrochloride salt. The material was used in the subsequent stepwithout purification.

Step e:

To a solution of((S)-3-((2-(((6-amino-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)-5-cyanobenzoicacid hydrochloride salt (142 mg, 0.17 mmol) in DMF (17 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (130 mg,0.68 mmol), 1-hydroxybenzotriazole hydrate (52 mg, 0.34 mmol), andN,N-diisopropylethylamine (300 μL, 1.7 mmol). The mixture was left tostir for 18 h and then concentrated in vacuo. The crude material waspurified by flash chromatography (SiO₂, 5% MeOH in DCM) to afford methyl(S)-1⁴-chloro-1⁵-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4⁵-cyano-5-oxo-2-oxa-6,12-diaza-1(1,2),4(1,3)-dibenzenacyclotridecaphane-11-carboxylate.

Step f:

To a biphasic solution of methyl(S)-1⁴-chloro-1⁵-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4⁵-cyano-5-oxo-2-oxa-6,12-diaza-1(1,2),4(1,3)-dibenzenacyclotridecaphane-11-carboxylate(116 mg, 0.156 mmol) in dioxane (2 mL) and water (1 mL) was addedlithium hydroxide monohydrate (7 mg, 0.17 mmol). After stirring at roomtemperature for 3 h, the reaction mixture was frozen and lyophilized toafford lithium(S)-1⁴-chloro-1⁵-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4⁵-cyano-5-oxo-2-oxa-6,12-diaza-1(1,2),4(1,3)-dibenzenacyclotridecaphane-11-carboxylate.The material was used in the subsequent step without purification.

Step g:

To a solution of lithium(S)-1⁴-chloro-1⁵-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4⁵-cyano-5-oxo-2-oxa-6,12-diaza-1(1,2),4(1,3)-dibenzenacyclotridecaphane-11-carboxylate(35 mg, 0.048 mmol) in DMF (1 mL) was added (R)-pyrrolidin-3-olhydrochloride salt (10 mg, 0.081 mmol), K₂CO₃ (38 mg, 0.27 mmol) and NaI(3 mg, 0.02 mmol). The resulting suspension was stirred at 70° C. for 18h. The reaction mixture was filtered, and the filtrate was concentratedin vacuo. The crude material was purified by reverse phase preparativeHPLC (CH₃CN—H₂O with 0.1% TFA) to obtain(S)-1⁴-chloro-4⁵-cyano-15-((3′-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-oxo-2-oxa-6,12-diaza-1(1,2),4(1,3)-dibenzenacyclotridecaphane-11-carboxylicacid as a trifluoroacetate salt. MS: (ES) m/z calculated forC₄₄H₄₉ClN₄O₇ [M+H]⁺ 781.3, found 781.5. ¹H NMR (400 MHz, Methanol-d₄) δ8.28 (s, 1H), 7.94 (s, 1H), 7.83 (s, 1H), 7.55 (s, 1H), 7.43 (d, J=7.6Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.02 (s, 1H),7.00 (d, J=7.7 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.65 (d, J=7.6 Hz, 1H),5.29 (s, 4H), 4.55-4.40 (m, 2H), 4.18 (d, J=13.1 Hz, 1H), 4.15-4.05 (m,2H), 3.90 (t, J=6.6 Hz, 1H), 3.84-3.62 (m, 1H), 3.59-3.43 (m, 2H),3.43-3.27 (m, 2H), 3.14-2.99 (m, 2H), 2.90 (d, J=12.4 Hz, 1H), 2.37-2.10(m, 4H), 2.10-2.01 (m, 4H), 2.00-1.89 (m, 2H), 1.85 (d, J=2.1 Hz, 3H),1.67-1.54 (m, 4H).

Example 4: Synthesis of(S)-2⁴-chloro-2⁵-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-11-oxo-4,10-diaza-1(3,5)-pyridina-2(1,2)-benzenacycloundecaphane-5-carboxylicacid

Step a:

To a cooled (−78° C.) solution of5-chloro-2-hydroxy-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde(0.42 g, 1.2 mmol) in DCM (20 mL) under nitrogen was slowly addedpyridine (0.5 mL) and trifluoromethansulfonic anhydride (0.4 mL, 2.4mmol). The solution was allowed to gradually warm to room temperatureand stir for 3 h. The reaction was carefully quenched by the slowaddition of saturated aqeuous NaHCO₃ until gas evolution subsided. Water(30 mL) was added and the aqueous mixture was extracted with DCM (2×25mL). The combined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, 100% hexane to 30% EtOAc in hexane) to afford4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenyltrifluoromethanesulfonate.

Step b:

A solution of4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenyltrifluoromethanesulfonate (180 mg, 0.37 mmol),(5-(methoxycarbonyl)pyridin-3-yl)boronic acid (81 mg, 0.44 mmol), andaqueous 2 M K₂CO₃ (0.4 mL, 0.20 mmol) in 1,2-dimethoxyethane (1.5 mL)was degassed with nitrogen for 10 min before Pd(PPh₃)₄ (85 mg, 0.074mmol) was added. After degassing for an additional 5 min, the solutionwas heated to 80° C. and allowed to stir for 1 h. After cooling to rt,water (5 mL) was added to the reaction mixture and the mixture wasextracted with EtOAc (5 mL×2). The combined organic layers were driedover MgSO₄, filtered, and concentrated in vacuo. Purification of thecrude material by flash chromatography (SiO₂, 100% hexane to 40% EtOAcin hexane) gave methyl5-(4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)nicotinate.

Step c:

To a biphasic solution of methyl5-(4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)nicotinate(121 mg, 0.26 mmol) in dioxane (4 mL) and water (1 mL) was added lithiumhydroxide monohydrate (16 mg, 0.39 mmol). The mixture was heated to 40°C. and allowed to stir for 30 min, at which time the reaction wascomplete. The crude reaction mixture was frozen and lyophilized toafford crude lithium5-(4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)nicotinate,which was used in the subsequent step without purification.

Step d:

To a solution of lithium5-(4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)nicotinate(117 mg, 0.26 mmol) and N′-Fmoc-L-lysine methyl ester hydrochloride salt(430 mg, 1.02 mmol) in DMF (6 mL) was added acetic acid (50 μL, 0.88mmol) and N,N-diisopropylethylamine (177 μL, 1.02 mmol). The mixture wasallowed to stir at room temperature for 30 min before sodiumtriacetoxyborohydride (163 mg, 0.77 mmol) was added in portions over 5min. The reaction mixture was stirred at room temperature for 18 h,before the mixture was concentrated in vacuo. The crude material wasre-diluted in MeOH, passed through a 0.45 μM syringe filter, andpurified by reverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA) toobtain(S)-5-(2-(((6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)nicotinicacid as a trifluoroacetate salt.

Step e:

(S)-5-((2-(((6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid (46 mg, 0.054 mmol) was dissolved in 10% piperidine in DMF (1.8mL), and the solution was stirred at room temperature for 15 min. Themixture was then concentrated in vacuo to afford(S)-5-(2-(((6-amino-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)nicotinicacid, which was used without further purification.

Step f:

To a solutionof(S)-5-(2-(((6-amino-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)nicotinicacid in DMF (6.2 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (50 mg,0.25 mmol), 1-hydroxybenzotriazole hydrate (20 mg, 0.125 mmol), andN,N-diisopropylethylamine (110 μL, 0.62 mmol). The mixture was left tostir for 18 h at rt and then concentrated in vacuo. The crude materialwas purified by flash chromatography (SiO₂, 10% MeOH in DCM) to affordmethyl(S)-2⁴-chloro-2⁵-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-11-oxo-4,10-diaza-1(3,5)-pyridina-2(1,2)-benzenacycloundecaphane-5-carboxylate.

Step g:

To a biphasic solution of methyl(S)-2⁴-chloro-2⁵-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-11-oxo-4,10-diaza-1(3,5)-pyridina-2(1,2)-benzenacycloundecaphane-5-carboxylate(20 mg, 0.034 mmol) in dioxane (1 mL) and water (0.5 mL) was addedlithium hydroxide monohydrate (19 mg, 0.45 mmol), and the mixture washeated to 40° C. After 1 h, the crude reaction mixture was passedthrough a 0.45 μM syringe filter and purified by reverse phasepreparative HPLC (CH₃CN—H₂O with 0.1% TFA) to obtain(S)-2⁴-chloro-2⁵-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-11-oxo-4,10-diaza-1(3,5)-pyridina-2(1,2)-benzenacycloundecaphane-5-carboxylicacid. MS: (ES) m/z calculated for C₃₃H₃₂ClN₃O₄ [M+H]⁺ 570.2, found570.1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.87 (s, 1H), 8.76 (s,1H), 8.62 (br s, 1H), 7.59-7.40 (m, 2H), 7.40-7.24 (m, 2H), 7.19 (s,2H), 7.06 (s, 2H), 6.93 (s, 2H), 5.48-5.25 (m, 2H), 3.76-3.48 (m, 2H),3.12-2.92 (m, 2H), 2.85-2.69 (m, 1H), 2.22 (s, 3H), 1.98-1.79 (m, 1H),1.73-1.31 (m, 5H).

Example 5: Synthesis of(S)-4⁴-chloro-7-(hydroxymethyl)-4⁵-((3′-(3-(4-hydroxypiperidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphan-13-one

Step a:

To a solution of lithium5-((4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinate(250 mg, 0.42 mmol) and tert-butyl (S)-(5-amino-6-hydroxyhexyl)carbamate(116 mg, 0.39 mmol) in MeOH (4 mL) was added Ti(Oi-Pr)₄ (185 μL, 0.63mmol). The mixture was allowed to stir at rt for 7 h before sodiumborohydride (117 mg, 3.08 mmol) was added in portions over 5 min. Thereaction mixture was stirred for 30 min and then concentrated in vacuo.The crude material was purified by flash chromatography (SiO₂, 100% DCMto 20% MeOH in DCM) to afford((S)-5-((2-(((6-((tert-butoxycarbonyl)amino)-1-hydroxyhexan-2-yl)amino)methyl)-4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid.

Step b:

To a solution of((S)-5-((2-(((6-((tert-butoxycarbonyl)amino)-1-hydroxyhexan-2-yl)amino)methyl)-4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid (286 mg, 0.35 mmol) in DCM (6 mL) was added 4 N HCl in dioxane(0.35 mL, 1.41 mmol). The mixture was allowed to stir at rt for 4 hbefore it was concentrated in vacuo to afford(S)-5-((2-(((6-amino-1-hydroxyhexan-2-yl)amino)methyl)-4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid hydrochloride salt. The material was used in the subsequent stepwithout purification.

Step c:

To a solution of(S)-5-((2-(((6-amino-1-hydroxyhexan-2-yl)amino)methyl)-4-chloro-5-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinicacid hydrochloride salt (167 mg, 0.20 mmol) in DMF (20 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (153 mg,0.81 mmol), 1-hydroxybenzotriazole hydrate (61 mg, 0.40 mmol), andN,N-diisopropylethylamine (420 μL, 2.40 mmol). The mixture was left tostir for 3 d at rt and then concentrated in vacuo. The crude materialwas re-diluted in MeOH, passed through a 0.45 μM syringe filter andpurified by reverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA) toobtain(S)-4⁴-chloro-4⁵-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-7-(hydroxymethyl)-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphan-13-oneas a trifluoroacetate salt.

Step d:

To a solution of(S)-4⁴-chloro-4⁵-((3′-(3-chloropropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-7-(hydroxymethyl)-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphan-13-onetrifluoroacetate salt (39 mg, 0.044 mmol) in DMF (1 mL) was added4-hydroxypiperidine (7 mg, 0.066 mmol), K₂CO₃ (24 mg, 0.18 mmol), andNaI (2 mg, 0.013 mmol). The resulting suspension was stirred at 80° C.for 12 h. The reaction mixture was filtered and concentrated in vacuo.The crude material was purified by reverse phase preparative HPLC(CH₃CN—H₂O with 0.1% TFA) to obtain(S)-4⁴-chloro-7-(hydroxymethyl)-4⁵-((3′-(3-(4-hydroxypiperidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-3-oxa-6,12-diaza-1(3,5)-pyridina-4(1,2)-benzenacyclotridecaphan-13-oneas a trifluoroacetate salt. MS: (ES) m/z calculated for C₄₃H₅₃ClN₄O₆[M+H]⁺ 757.4, found 757.7. ¹H NMR (400 MHz, Methanol-d₄) δ 8.81 (d,J=2.1 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H), 8.48 (dt, J=2.2, 1.1 Hz, 1H),7.49 (dd, J=7.7, 1.7 Hz, 1H), 7.40 (s, 1H), 7.23 (t, J=7.6 Hz, 1H),7.21-7.13 (m, 1H), 7.06 (dd, J=7.6, 1.4 Hz, 1H), 7.01 (d, J=3.5 Hz, 1H),6.92 (d, J=8.3 Hz, 1H), 6.68 (d, J=37.7 Hz, 1H), 5.32 (s, 2H), 5.30 (s,2H), 4.19 (d, J=11.8 Hz, 1H), 4.08 (tq, J=6.3, 3.5 Hz, 2H), 3.71 (dd,J=11.2, 4.1 Hz, 1H), 3.69-3.61 (m, 2H), 3.62-3.43 (m, 2H), 2.96-2.84 (m,2H), 2.84-2.73 (m, 1H), 2.69-2.59 (m, 2H), 2.33-2.17 (m, 2H), 2.10 (d,J=1.4 Hz, 3H), 2.09-1.98 (m, 3H), 1.93-1.81 (m, 4H), 1.80-1.66 (m, 5H),1.66-1.48 (m, 5H).

Example 6: Synthesis of(S)-16-chloro-17-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6-oxo-3,4,5,6,7,8,9,10,11,12,13,14-dodecahydro-2H-benzo[b][1]oxa[5,11]diazacyclohexadecine-12-carboxylicacid

Step a:

Methyl 5-bromovalerate (0.18 mL, 1.2 mmol) was added dropwise withstirring to a mixture of 5-chloro-2hydroxy-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxybenzaldehyde (353 mg,1.0 mmol) and cesium carbonate (652 mg, 2.0 mmol) in DMF (2 mL). Themixture was stirred at room temperature overnight. The reaction mixturewas diluted with water (20 mL) and extracted with EtOAc (3×20 mL). Thecombined organic layers were washed with brine (20 mL), dried overMgSO₄, filtered, and concentrated. Purification by flash chromatographyon silica (0-50% EtOAc/hexanes) gave methyl5-(4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)pentanoate.

Step b:

To a stirred solution of methyl5-(4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)pentanoate(280 mg, 0.60 mmol) in THF (8 mL) was added a solution of lithiumhydroxide monohydrate (76 mg, 1.8 mmol) in water (2 mL). The reactionmixture was stirred at room temperature overnight. The reaction mixturewas diluted with 1 M HCl (10 mL) and extracted with EtOAc (3×10 mL). Thecombined organic layers were washed with brine (10 mL), dried overMgSO₄, filtered, and concentrated to give5-(4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)pentanoicacid, which was used without further purification.

Step c:

To a solution of5-(4-chloro-2-formyl-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)pentanoicacid (254 mg, 0.56 mmol) and N′-Fmoc-L-lysine methyl ester hydrochloride(1.7 g, 2.8 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (0.5mL). The mixture was stirred at room temperature, and sodiumtriacetoxyborohydride (361 mg, 1.7 mmol) was added slowly in portions.The reaction mixture was stirred at room temperature overnight.Purification by preparative HPLC (H₂O/MeCN, with 0.1% TFA) gave(S)-5-(2-(((6-amino-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)pentanoicacid as the bis-TFA salt.

Step d:

To a stirred solution of(S)-5-(2-(((6-amino-1-methoxy-1-oxohexan-2-yl)amino)methyl)-4-chloro-5-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)pentanoicacid (62 mg, 0.075 mmol) in DMF (7.5 mL) were addedN,N-diisopropylethylamine (0.13 mL, 0.75 mmol), 1-hydroxybenzotriazolehydrate (23 mg, 0.15 mmol), andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg,0.30 mmol). The reaction mixture was stirred at room temperatureovernight, then concentrated. Purification by preparative HPLC(H₂O/MeCN, with 0.1% TFA) gave methyl(S)-16-chloro-17-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6-oxo-3,4,5,6,7,8,9,10,11,12,13,14-dodecahydro-2H-benzo[b][1]oxa[5,11]diazacyclohexadecine-12-carboxylateas the TFA salt.

Step e:

To a stirred solution of methyl(S)-16-chloro-17-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6-oxo-3,4,5,6,7,8,9,10,11,12,13,14-dodecahydro-2H-benzo[b][1]oxa[5,11]diazacyclohexadecine-12-carboxylate(10 mg, 0.015 mmol) in THF (0.8 mL) was added a solution of lithiumhydroxide monohydrate (3 mg, 0.060 mmol) in water (0.2 mL). The reactionmixture was stirred at room temperature overnight. Purification bypreparative HPLC (H₂O/MeCN, with 0.1% TFA) gave(S)-16-chloro-17-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6-oxo-3,4,5,6,7,8,9,10,11,12,13,14-dodecahydro-2H-benzo[b][1]oxa[5,11]diazacyclohexadecine-12-carboxylicacid as the TFA salt. MS: (ES) m/z calculated for C₃₂H₃₈ClN₂O₅ [M+H]⁺565.2, found 565.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (br s, 2H), 7.81(t, 1H, J=5.6 Hz), 7.52 (dd, 1H, J=1.2, 7.6 Hz), 7.48-7.41 (m, 3H),7.39-7.34 (m, 1H), 7.32-7.26 (m, 3H), 7.21 (dd, 1H, J=1.2, 8.0 Hz), 5.31(s, 2H), 4.20-4.10 (m, 2H), 4.04-3.94 (m, 2H), 3.90-3.84 (m, 1H),3.23-3.12 (m, 1H), 3.09-2.98 (m, 1H), 2.22 (s, 3H), 2.18-2.07 (m, 2H),2.04-1.93 (m, 1H), 1.92-1.82 (m, 1H), 1.79-1.66 (m, 4H), 1.53-1.40 (m,3H), 1.34-1.20 (m, 1H).

Reverse phase HPLC conditions used for determination of retention timesin Table 1:

-   -   Column: ZORBAX (SB-C18 2.1×50 mm, 5 μm)    -   Mobile phase A: 95% H₂O, 5% MeCN (with 0.1% Formic Acid)    -   Mobile phase B: 5% H₂O, 95% MeCN (with 0.1% Formic Acid)    -   Flow rate: 1.0 mL/min    -   Gradient: 20 to 100% B in 3.5 min

Example 7: Enzyme-Linked Immunosorbent Assay—ELISA

96 Well plates were coated with 1 μg/mL of human PD-L1 (obtained fromR&D) in PBS overnight at 4° C. The wells were then blocked with 2% BSAin PBS (W/V) with 0.05% TWEEN-20 for 1 hour at 37° C. The plates werewashed 3 times with PBS/0.05% TWEEN-20 and the compounds were serialdiluted (1:5) in dilution medium and added to the ELISA plates. HumanPD-1 and biotin 0.3 μg/mL (ACRO Biosystems) were added and incubated for1 hour at 37° C. then washed 3 times with PBS/0.05% TWEEN-20. A secondblock was performed with 2% BSA in PBS (W/V)/0.05% TWEEN-20 for 10 minat 37° C. and was washed 3 times with PBS/0.05% TWEEN-20.Streptavidin-HRP was added for 1 hour at 37° C. then washed 3 times withPBS/0.05% TWEEN-20. TMB substrate was added and reacted for 20 min at37° C. A stop solution (2 N aqueous H₂SO₄) was added. The absorbance wasread at 450 nm using a micro-plate spectrophotometer. The results areshown in Table 1.

Compounds in Table 1 were prepared by methods as described in theExamples and evaluated according to the assay above. The IC₅₀ of thecompounds are presented in Table 1 as follows:

+, 20000 nM≥IC₅₀≥500 nM;++, 500 nM≥IC₅₀≥100 nM;+++, 100 nM>IC₅₀.

TABLE 1 ELISA RP-HPLC Compound IC₅₀ MS R_(t) Id Structure (nM) (M+H)⁺(min) 1.001

+++ 648.2 2.1 1.002

+++ 658.2 2.3 1.003

+++ 618.2 2.3 1.004

+++ 771.6 1.6 1.005

+ 706.2 2.6 1.006

++ 601.2 2.1 1.007

++ 630.2 2.3 1.008

++ 602.1 2.3 1.009

+ 572.1 2.3 1.010

++ 586.1 2.0 1.011

++ 614.2 2.1 1.012

++ 565.2 2.2 1.013

+ 570.1 2.3 1.014

+++ 688.2 2.2 1.015

+++ 601.2 2.4 1.016

+++ 600.1 2.3 1.017

+++ 758.7 1.8 1.018

+++ 758.7 1.8 1.019

+++ 800.7 1.9 1.020

+++ 743.5 1.7 1.021

+++ 797.5 2.0 1.022

+++ 796.8 2.4 1.023

+++ 782.8 2.2 1.024

+++ 743.2 2.3 1.025

+++ 759.3 1.9

What is claimed is:
 1. A compound of Formula (I) or Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: R is selectedfrom the group consisting of H, halogen, CN, C₁₋₃ haloalkyl, C₁₋₃ alkyland C₁₋₃ alkoxy; R¹ is selected from the group consisting of halogen,C₅₋₈ cycloalkyl, C₆₋₁₀ aryl and thienyl, wherein the C₆₋₁₀ aryl andthienyl are optionally substituted with 1 to 5 R^(1a) substituents; eachR^(1a) is independently selected from the group consisting of halogen,—CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a), —OC(O)NR^(a)R^(b),—NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c), —NR^(a)—C(O)NR^(a)R^(b),—NR^(a)R^(b), —OR^(a), —O—X¹—OR^(a), —O—X¹—CO₂R^(a),—O—X¹—CONR^(a)R^(b), —X¹—OR^(a), —X¹—NR^(a)R^(b), —X¹—CO₂R^(a),—X¹—CONR^(a)R^(b), —SF₅, and —S(O)₂NR^(a)R^(b), wherein each X¹ is aC₁₋₄ alkylene; each R^(a) and R^(b) is independently selected fromhydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the samenitrogen atom can be combined with the nitrogen atom to form a five orsix-membered ring having from 0 to 2 additional heteroatoms as ringmembers selected from N, O or S, wherein the five or six-membered ringis optionally substituted with oxo; each R^(c) is independently selectedfrom the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl andC₁₋₈ haloalkyl; and optionally when two R^(1a) substituents are onadjacent atoms, they are combined to form a fused five, six orseven-membered carbocyclic or heterocyclic ring optionally substitutedwith from 1 to 3 substituents independently selected from halogen, oxo,C₁₋₈ haloalkyl and C₁₋₈ alkyl; or R¹ is

wherein each of R^(1b), R^(1c), R^(1d) and R^(1e) is independentlyselected from the group consisting of H, halogen, CF₃, CN, C₁₋₄ alkyland —O—C₁₋₄ alkyl, wherein the C₁₋₄ alkyl and —O—C₁₋₄ alkyl areoptionally further substituted with halogen, hydroxyl, methoxy orethoxy; L is a linking group selected from the group consisting of:

wherein each of the subscripts q is independently 1, 2, 3 or 4, and L isoptionally further substituted with one or two members selected from thegroup consisting of halogen, hydroxy, C₁₋₃ alkyl, —O—C₁₋₃ alkyl, C₁₋₃hydroxyalkyl, C₁₋₃ haloalkyl and —CO₂H; Z is selected from the groupconsisting of azetidinyl, pyrollidinyl, piperidinyl, morpholinyl, 33pyridyl, pyrimidinyl, guanidinyl, quinuclidine, and8-azabicyclo[3.2.1]octane, each of 34 which is optionally substitutedwith from 1 to 3 groups independently selected from halogen, hydroxy,C₁₋₃ alkyl, —NH₂, —NHC₁₋₃alkyl, —N(C₁₋₃alkyl)₂, —O—C₁₋₃ alkyl, C₁₋₃hydroxyalkyl, C₁₋₃ haloalkyl and —CO₂H; or Z is selected from the groupconsisting of —CO₂R^(z1) and —NR^(z1)R^(z2); wherein R^(z1) is selectedfrom the group consisting of H, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈hydroxyalkyl; and R^(z2) is selected from —C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₁₋₈ alkyl-COOH, C₁₋₈ alkyl-OH, C₁₋₈ alkyl-CONH₂, C₁₋₈ alkyl-SO₂NH₂,C₁₋₈ alkyl-PO₃H₂, C₁₋₈ alkyl-C(O)NHOH, —C(O)—C₁₋₈alkyl-OH,—C(O)—C₁₋₈alkyl-COOH, C₃₋₁₀ cycloalkyl, —C₃₋₁₀ cycloalkyl-COOH, —C₃₋₁₀cycloalkyl-OH, C₄₋₈ heterocyclyl, —C₄₋₈ heterocyclyl-COOH, —C₄₋₈heterocyclyl-OH, —C₁₋₈ alkyl-C₄₋₈ heterocyclyl, —C₁₋₈ alkyl-C₃₋₁₀cycloalkyl, C₅₋₁₀ heteroaryl and —C₁₋₈alkyl-C₅₋₁₀ heteroaryl; eachR^(2a), R^(2b) and R^(2c) is independently selected from the groupconsisting of H, halogen, —CN, —R^(d), —CO₂R^(e), —CONR^(e)R^(f),—OC(O)NR^(e)R^(f), —NR^(f)C(O)R^(e), —NR^(f)C(O)₂R^(d),—NR^(e)—C(O)NR^(e)R^(f), —NR^(e)R^(f), —OR^(e), —X²—OR^(e),—X²—NR^(e)R^(f), —X²—CO₂R^(e), —SF₅, and —S(O)₂NR^(e)R^(f), wherein eachX² is a C₁₋₄ alkylene; each R^(e) and R^(f) is independently selectedfrom hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to thesame nitrogen atom can be combined with the nitrogen atom to form a fiveor six-membered ring having from 0 to 2 additional heteroatoms as ringmembers selected from N, O and S, and optionally substituted with oxo;each R^(d) is independently selected from the group consisting of C₁₋₈alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl; R³ is selected from the groupconsisting of —NR^(g)R^(h) and C₄₋₁₂ heterocyclyl, wherein the C₄₋₁₂heterocyclyl is optionally substituted with 1 to 6 R^(3a); each R^(3a)is independently selected from the group consisting of halogen, —CN,—R^(i), —CO₂R^(j), —CONR^(j)R^(k), —CONHC₁₋₆ alkyl-OH, —C(O)R^(j),—OC(O)NR^(j)R^(k), —NR^(j)C(O)R^(k), —NR^(j)C(O)₂R^(k), —CONHOH, —PO₃H₂,—NR^(j)—X³—C(O)₂R^(k), —NRC(O)NR^(j)R^(k), —NR^(j)R^(k), —OR^(j),—S(O)₂NR^(j)R^(k), —O—X³—OR^(j), —O—X³—NR^(j)R^(k), —O—X³—CO₂R,—O—X³—CONR^(j)R^(k), —X³—OR^(j), —X³—NR^(j)R^(k), —X³—CO₂R^(j),—X³—CONR^(j)R^(k), —X³—CONHSO₂R^(j) and SF₅; wherein X³ is C₁₋₆ alkyleneand is optionally further substituted with OH, SO₂NH₂, CONH₂, C(O)NHOH,PO₃H₂, COO—C₁₋₈alkyl or CO₂H, wherein each R^(j) and R^(k) isindependently selected from hydrogen, C₁₋₈ alkyl optionally substitutedwith 1 to 2 substituents selected from OH, SO₂NH₂, CONH₂, C(O)NHOH,PO₃H₂, B(OH)₂, COO—C₁₋₈alkyl or CO₂H, and C₁₋₈ haloalkyl optionallysubstituted with 1 to 2 substituents selected from OH, SO₂NH₂, CONH₂,C(O)NHOH, PO₃H₂, COO—C₁₋₈alkyl or CO₂H, or when attached to the samenitrogen atom R^(j) and R^(k) can be combined with the nitrogen atom toform a five or six-membered ring having from 0 to 2 additionalheteroatoms as ring members selected from N, O or S, and optionallysubstituted with oxo; each R^(i) is independently selected from thegroup consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl each ofwhich may be optionally substituted with OH, SO₂NH₂, CONH₂, C(O)NHOH,PO₃H₂, COO—C₁₋₈alkyl or CO₂H; R^(g) is selected from the groupconsisting of H, C₁₋₈ haloalkyl and C₁₋₈ alkyl; R^(h) is selected fromC₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ hydroxyalkyl, C₁₋₈alkyl-CO₂R^(j),C₁₋₈alkyl-CONR^(j)R^(k), C₁₋₈alkyl-CONHSO₂R_(j), C₁₋₈alkyl-SO₂NR^(j)R^(k), C₁₋₈ alkyl-PO₃H₂, C₁₋₈ alkyl-C(O)NHOH, C₁₋₈alkyl-NR^(j)R^(k), —C(O)R^(j), C₃₋₁₀ cycloalkyl, —C₃₋₁₀cycloalkyl-COOR^(j), —C₃₋₁₀ cycloalkyl-OR^(j), C₄₋₈ heterocyclyl, —C₄₋₈heterocyclyl-COOR^(j), —C₄₋₈ heterocyclyl-OR^(j), —C₁₋₈ alkyl-C₄₋₈heterocyclyl, —C(═O)OC₁₋₈ alkyl-C₄₋₈ heterocyclyl, —C₁₋₈ alkyl-C₃₋₁₀cycloalkyl, C₅₋₁₀ heteroaryl, —C₁₋₈alkyl-C₅₋₁₀ heteroaryl, —C₁₋₈alkyl-C₆₋₁₀ aryl, —C₁₋₈ alkyl-(C═O)—C₆₋₁₀ aryl, —CO₂—C₁₋₈ alkyl-O₂C—C₁₋₈alkyl, —C₁₋₈ alkyl-NH(C═O)—C₂₋₈ alkenyl, —C₁₋₈ alkyl-NH(C═O)—C₁₋₈ alkyl,—C₁₋₈ alkyl-NH(C═O)—C₂₋₈ alkynyl, —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈alkyl-COOR^(j), and —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-OR^(j) optionallysubstituted with CO₂H; or R^(h) combined with the N to which it isattached is a mono-, di- or tri-peptide comprising 1-3 natural aminoacids and 0-2 non-natural amino acids, wherein the non-naturalaminoacids have an alpha carbon substituent selected from the groupconsisting of C₂₋₄ hydroxyalkyl, C₁₋₃ alkyl-guanidinyl, and C₁₋₄alkyl-heteroaryl, the alpha carbon of each natural or non-natural aminoacid is optionally further substituted with a methyl group, and theterminal moiety of the mono-, di-, or tri-peptide is selected from thegroup consisting of C(O)OH, C(O)O—C₁₋₆ alkyl, and PO₃H₂, wherein theC₁₋₈ alkyl portions of R^(h) are optionally further substituted withfrom 1 to 3 substituents independently selected from OH, COOH, SO₂NH₂,CONH₂, C(O)NHOH, COO—C₁₋₄ alkyl, PO₃H₂ and C₅₋₆ heteroaryl optionallysubstituted with 1 to 2 C₁₋₃ alkyl substituents, the C₅₋₁₀ heteroaryland the C₆₋₁₀ aryl portions of R^(h) are optionally substituted with 1to 3 substituents independently selected from OH, B(OH)₂, COOH, SO₂NH₂,CONH₂, C(O)NHOH, PO₃H₂, COO—C₁₋₈-alkyl, C₁₋₄alkyl, C₁₋₄alkyl-OH,C₁₋₄alkyl-SO₂NH₂, C₁₋₄alkyl CONH₂, C₁₋₄alkyl-C(O)NHOH, C₁₋₄alkyl-PO₃H₂,C₁₋₄alkyl-COOH, and phenyl; the C₄₋₈ heterocyclyl and C₃₋₁₀ cycloalkylportions of R^(h) are optionally substituted with 1 to 4 R^(h1)substituents; each R^(h1) substituent is independently selected fromC₁₋₄ alkyl, C₁₋₄ alkyl-OH, C₁₋₄ alkyl-COOH, C₁₋₄ alkyl-SO₂NH₂, C₁₋₄alkyl CONH₂, C₁₋₄ alkyl-C(O)NHOH, C₁₋₄ alkyl-PO₃H, OH, COO—C₁₋₈ alkyl,COOH, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂, B(OH)₂ and oxo; R⁴ is selectedfrom the group consisting of O—C₁₋₈ alkyl, O—C₁₋₈ haloalkyl, C₆₋₁₀ aryl,C₅₋₁₀ heteroaryl, —O—C₁₋₄ alkyl-C₄₋₇ heterocycloalkyl, —O—C₁₋₄alkyl-C₆₋₁₀aryl and —O—C₁₋₄ alkyl-C₅₋₁₀ heteroaryl, each of which isoptionally substituted with 1 to 5 R^(4a); each R^(4a) is independentlyselected from the group consisting of halogen, —CN, —R^(m), —CO₂R^(n),—CONR^(n)R^(p), —C(O)R^(n), —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p),—NR^(n)C(O)₂R^(m), —NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n),—O—X⁴—OR^(n), —O—X⁴—NR^(n)R^(p), —O—X⁴—CO₂R^(n), —O—X⁴—CONR^(n)R^(p),—X⁴—OR^(n), —X⁴—NR^(n)R^(p), —X⁴—CO₂R^(n), —X⁴—CONR^(n)R^(p), —SF₅,—S(O)₂R^(n)R^(p), —S(O)₂NR^(n)R^(p), C₃₋₇ cycloalkyl and C₄₋₇heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl rings areoptionally substituted with 1 to 5 R^(t), wherein each R^(t) isindependently selected from the group consisting of C₁₋₈ alkyl,C₁₋₈haloalkyl, —CO₂R^(n), —CONR^(n)R^(p), —C(O)R^(n), —OC(O)NR^(n)R^(p),—NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m), —NR^(n)—C(O)NR^(n)R^(p),—NR^(n)R^(p), —OR^(n), —O—X⁴—OR^(n), —O—X⁴—NR^(n)R^(p), —O—X⁴—CO₂R^(n),—O—X⁴—CONR^(n)R^(p), —X⁴—OR^(n), —X⁴—NR^(n)R^(p), —X⁴—CO₂R^(n),—X⁴—CONR^(n)R^(p), —SF₅, and —S(O)₂NR^(n)R^(p); wherein each X⁴ is aC₁₋₆ alkylene; each R^(n) and R^(p) is independently selected fromhydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the samenitrogen atom can be combined with the nitrogen atom to form a five orsix-membered ring having from 0 to 2 additional heteroatoms as ringmembers selected from N, O or S, and optionally substituted with oxo;each R^(m) is independently selected from the group consisting of C₁₋₈alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl; and optionally when two R^(4a)substituents are on adjacent atoms, they are combined to form a fusedfive or six-membered carbocyclic or heterocyclic ring optionallysubstituted with oxo; and wherein R³ and R⁴ are joined to form a 12- to20-membered macrocycle; n is 0, 1, 2 or 3; each R⁵ is independentlyselected from the group consisting of halogen, —CN, —R^(q), —CO₂R^(r),—CONR^(r)R^(s), —C(O)R^(r), —OC(O)NR^(r)R^(s), —NR^(r)C(O)R^(s),—NR^(r)C(O)₂R^(q), —NR^(r)—C(O)NR^(r)R^(s), —NR^(r)R^(s), —OR^(r),—O—X⁵—OR^(r), —O—X⁵—NR^(r)R^(s), —O—X⁵—CO₂R^(r), —O—X⁵—CONR^(r)R^(s),—X⁵—OR^(r), —X⁵—NR^(r)R^(s), —X⁵—CO₂R^(r), —X⁵—CONR^(r)R^(s), —SF₅,—S(O)₂NR^(r)R^(s), wherein each X⁵ is a C₁₋₄ alkylene; each R^(r) andR^(s) is independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈haloalkyl, or when attached to the same nitrogen atom can be combinedwith the nitrogen atom to form a five or six-membered ring having from 0to 2 additional heteroatoms as ring members selected from N, O or S, andoptionally substituted with oxo; each R^(q) is independently selectedfrom the group consisting of C₁₋₈ alkyl, and C₁₋₈ haloalkyl; R^(6a) andR^(6c) are each independently selected from the group consisting of H,C₁₋₄ alkyl and C₁₋₄ haloalkyl; m is 0, 1, 2, 3 or 4; each R^(6b) isindependently selected from the group consisting of F, C₁₋₄ alkyl,O—R^(u), C₁₋₄ haloalkyl, NR^(u)R^(v), wherein each R^(u) and R^(v) isindependently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, orwhen attached to the same nitrogen atom can be combined with thenitrogen atom to form a five or six-membered ring having from 0 to 2additional heteroatoms as ring members selected from N, O or S, andoptionally substituted with oxo.
 2. A compound of claim 1, havingFormula (I).
 3. A compound of claim 1, having Formula (II).
 4. Acompound of claim 1, having Formula (Ia) or Formula (IIa)

or a pharmaceutically acceptable salt thereof; wherein: W is N or C(R⁹);X, Y and V are each independently selected from the group consisting ofa bond, O, NH, N(CH₃), C(O), methylene and ethylene, wherein themethylene and ethylene are optionally substituted with one or twoR^(7a); R¹ is selected from the group consisting of C₆₋₁₀ aryl andthienyl, each of which is optionally substituted with 1 to 5 R^(1a)substituents; each R^(7a) and R^(7b) is independently selected from thegroup consisting of H, C₁₋₆ alkyl, CO₂H, CH₂OH, —CO₂—(C₁₋₆alkyl) andPO₃H₂, wherein C₁₋₆ alkyl is optionally substituted with one or twomembers selected from halogen, OH, NH₂, CN, and CO₂H; each R^(8a) andR^(8b) is independently selected from the group consisting of H and C₁₋₆alkyl, optionally substituted with halogen, OH, NH₂, CN, and CO₂H; andR⁹ a member selected from the group consisting of H, halogen, CN, C₁₋₆alkyl, —O—C₁₋₆ alkyl, —SO₂(C₁₋₆ alkyl), —C₁₋₆ alkyl-CO₂H, —C₁₋₆alkyl-CO₂—C₁₋₆ alkyl, —C₁₋₆ alkyl-C(O)NH₂, —C₁₋₆ alkyl-C(O)NHC₁₋₆ alkyland —C₁₋₆ alkyl-C(O)N(C₁₋₆ alkyl)₂.
 5. A compound of claim 4, havingFormula (Ia).
 6. A compound of claim 4, having Formula (IIa).
 7. Acompound of claim 1, having Formula (Ib) or Formula (IIb)

or a pharmaceutically acceptable salt thereof; wherein: W is N or C(R⁹);X, Y and V are each independently selected from the group consisting ofa bond, O, NH, N(CH₃), C(O), methylene and ethylene, wherein themethylene and ethylene are optionally substituted with one or twoR^(7a); each R^(7a) and R^(7b) is independently selected from the groupconsisting of H, C₁₋₆ alkyl, CO₂H, CH₂OH, —CO₂—(C₁₋₆alkyl) and PO₃H₂,wherein C₁₋₆ alkyl is optionally substituted with one or two membersselected from halogen, OH, NH₂, CN, and CO₂H; each R^(8a) and R^(8b) isindependently selected from the group consisting of H and C₁₋₆ alkyl,optionally substituted with halogen, OH, NH₂, CN, and CO₂H; and R⁹ amember selected from the group consisting of H, halogen, CN, C₁₋₆ alkyl,—O—C₁₋₆ alkyl, —SO₂(C₁₋₆ alkyl), —C₁₋₆ alkyl-CO₂H, —C₁₋₆ alkyl-CO₂—C₁₋₆alkyl, —C₁₋₆ alkyl-C(O)NH₂, —C₁₋₆ alkyl-C(O)NHC₁₋₆ alkyl and —C₁₋₆alkyl-C(O)N(C₁₋₆ alkyl)₂.
 8. A compound of claim 7, having Formula (Ib).9. A compound of claim 7, having Formula (IIb).
 10. A compound of claim1, having Formula (Ic) or Formula (IIc)

or a pharmaceutically acceptable salt thereof; wherein: X⁹ is C₁₋₈alkylene; X, Y and V are each independently selected from the groupconsisting of a bond, O, NH, N(CH₃), C(O), methylene and ethylene,wherein the methylene and ethylene are optionally substituted with oneor two R^(7a); each R^(7a) and R^(7b) is independently selected from thegroup consisting of H, C₁₋₆ alkyl, CO₂H, CH₂OH, —CO₂—(C₁₋₆alkyl) andPO₃H₂, wherein C₁₋₆ alkyl is optionally substituted with one or twomembers selected from halogen, OH, NH₂, CN, and CO₂H; and each R^(8a)and R^(8b) is independently selected from the group consisting of H andC₁₋₆ alkyl, optionally substituted with halogen, OH, NH₂, CN, and CO₂H.11. A compound of claim 10, having Formula (Ic).
 12. A compound of claim10, having Formula (IIc).
 13. The compound of claim 1 or apharmaceutically acceptable salt thereof wherein the macrocycle formedby joining R³ and R⁴ is a 15- or 16-membered macrocycle.
 14. A compoundof claim 1, having Formula (Ia1) or Formula (IIa1)

or a pharmaceutically acceptable salt thereof; wherein: W is N or C(R⁹);R¹ is selected from the group consisting of C₆₋₁₀ aryl and thienyl, eachof which is optionally substituted with 1 to 5 R^(1a) substituents; eachR^(7a) and R^(7b) is independently selected from the group consisting ofH, C₁₋₆ alkyl, CO₂H, —CO₂—(C₁₋₆alkyl) and PO₃H₂, wherein C₁₋₆ alkyl isoptionally substituted with one or two members selected from halogen,OH, NH₂, CN, and CO₂H; and R⁹ a member selected from the groupconsisting of H, halogen, CN, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —SO₂(C₁₋₆alkyl), —C₁₋₆ alkyl-CO₂H, —C₁₋₆ alkyl-CO₂—C₁₋₆ alkyl, —C₁₋₆alkyl-C(O)NH₂, —C₁₋₆ alkyl-C(O)NHC₁₋₆ alkyl and —C₁₋₆ alkyl-C(O)N(C₁₋₆alkyl)₂.
 15. A compound of claim 14, having Formula (Ia1).
 16. Acompound of claim 14, having Formula (IIa1).
 17. A compound of claim 14,wherein R⁹ is CN.
 18. A compound of claim 14, wherein each R^(7a) andR^(7b) is independently selected from the group consisting of H, CO₂H,and CH₂OH.
 19. A compound of claim 1, having Formula (Ib1) or Formula(IIb1):

or a pharmaceutically acceptable salt thereof; wherein: W is N or C(R⁹);each R^(7a) and R^(7b) is independently selected from the groupconsisting of H, C₁₋₆ alkyl, CO₂H, —CO₂—(C₁₋₆alkyl) and PO₃H₂, whereinC₁₋₆ alkyl is optionally substituted with one or two members selectedfrom halogen, OH, NH₂, CN, and CO₂H; R⁹ a member selected from the groupconsisting of H, halogen, CN, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —SO₂(C₁₋₆alkyl), —C₁₋₆ alkyl-CO₂H, —C₁₋₆ alkyl-CO₂—C₁₋₆ alkyl, —C₁₋₆alkyl-C(O)NH₂, —C₁₋₆ alkyl-C(O)NHC₁₋₆ alkyl and —C₁₋₆ alkyl-C(O)N(C₁₋₆alkyl)₂.
 20. A compound of claim 19, having Formula (Ib1).
 21. Acompound of claim 19, having Formula (IIb1).
 22. A compound of claim 19,wherein R⁹ is CN.
 23. A compound of claim 19, wherein each R^(7a) andR^(7b) is independently selected from the group consisting of H, CO₂H,and CH₂OH.
 24. A compound of claim 1, having Formula (Ic1) or Formula(IIc1):

or a pharmaceutically acceptable salt thereof; wherein: W is N or C(R⁹);each R^(7a) and R^(7b) is independently selected from the groupconsisting of H, C₁₋₆ alkyl, CO₂H, CH₂OH, —CO₂—(C₁₋₆alkyl) and PO₃H₂,wherein C₁₋₆ alkyl is optionally substituted with one or two membersselected from halogen, OH, NH₂, CN, and CO₂H; R⁹ a member selected fromthe group consisting of H, halogen, CN, C₁₋₆ alkyl, —O—C₁₋₆ alkyl,—SO₂(C₁₋₆ alkyl), —C₁₋₆ alkyl-CO₂H, —C₁₋₆ alkyl-CO₂—C₁₋₆ alkyl, —C₁₋₆alkyl-C(O)NH₂, —C₁₋₆ alkyl-C(O)NHC₁₋₆ alkyl and —C₁₋₆ alkyl-C(O)N(C₁₋₆alkyl)₂.
 25. A compound of claim 19, having Formula (Ic1).
 26. Acompound of claim 19, having Formula (IIc1).
 27. A compound of claim 19,wherein R⁹ is CN.
 28. A compound of claim 19, wherein each R^(7a) andR^(7b) is independently selected from the group consisting of H, CO₂H,and CH₂OH.
 29. The compound of any one of claims 1-6 or 13-16, or apharmaceutically acceptable salt thereof wherein R¹ is phenyl,optionally substituted with 1 to 3 R^(1a) substituents.
 30. The compoundof any one of claims 1-6 or 13-16, or a pharmaceutically acceptable saltthereof wherein R¹ is phenyl, optionally substituted with 1 to 3 R^(1a)substituents 3 wherein each R^(1a) is independently selected fromhalogen, C₁₋₈ alkyl, O—C₁₋₈ alkyl, O—C₁₋₈ haloalkyl, —NR^(a)R^(b), andCN, and optionally when two R^(1a) substituents are on adjacent atoms,they are combined to form a fused six-membered heterocyclic ringoptionally substituted with from 1 to 3 substituents independentlyselected from oxo, C₁₋₈ haloalkyl and C₁₋₈ alkyl.
 31. The compound ofany one of claims 1-6 or 13-16, or a pharmaceutically acceptable saltthereof wherein R¹ is selected from the group consisting of:


32. The compound of any one of claims 1, 2, 3, 7-13, or 19-26, or apharmaceutically acceptable salt thereof, wherein Z-L- is a memberselected from the group consisting of:


33. The compound of any one of claims 1, 2, 3, 7-13, or 19-26, or apharmaceutically acceptable salt thereof, wherein Z-L- is a memberselected from the group consisting of:


34. The compound of any one of claims 1, 2, 3, 7-13, or 19-26, or apharmaceutically acceptable salt thereof, wherein Z-L- is a memberselected from the group consisting of:


35. The compound of any one of claims 1-6 or 13-16, or apharmaceutically acceptable salt thereof wherein R¹ is phenyl,optionally substituted with F.
 36. The compound of any one of claims 1to 31 or a pharmaceutically acceptable salt thereof, wherein eachR^(2a), R^(2b) and R^(2c) is independently selected from the groupconsisting of H, halogen, —CN, —R^(d), —NR^(e)R^(f), —OR^(e),—X²—OR^(e), —X²—NR^(e)R^(f), wherein X² is C₁-4 alkylene; each R^(e) andR^(f) is independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈haloalkyl, or when attached to the same nitrogen atom can be combinedwith the nitrogen atom to form a five or six-membered ring having from 0to 2 additional heteroatoms as ring members selected from N, O or S, andoptionally substituted with oxo; each R^(d) is independently selectedfrom the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₁₋₈haloalkyl.
 37. The compound of any one of claims 1 to 31 or apharmaceutically acceptable salt thereof, wherein R^(2b) and R^(2c) areboth H and R^(2a) is selected from the group consisting of halogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₁₋₃ haloalkyl, —CN, —OMe and OEt.
 38. The compoundof any one of claims 1 to 31 or a pharmaceutically acceptable saltthereof, wherein R^(2b) and R^(2c) are both H and R^(2a) is halogen. 39.The compound of any one of claims 1 to 31 or a pharmaceuticallyacceptable salt thereof, wherein R^(2b) and R^(2c) are both H and R^(2a)is Cl.
 40. The compound of any one of claims 1 to 39, or apharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2 andeach R⁵ is independently selected from the group consisting of halogen,—CN, —R^(m), —NR^(n)R^(p), and —OR^(n), wherein each R^(n) and R^(p) isindependently selected from hydrogen, C₁₋₈ alkyl and C₁₋₈ haloalkyl andeach R^(m) is independently selected from the group consisting of C₁₋₈alkyl and C₁₋₈ haloalkyl.
 41. The compound of any one of claims 1 to 39,or a pharmaceutically acceptable salt thereof, wherein n is
 0. 42. Thecompound of any one of claims 1 to 41, or a pharmaceutically acceptablesalt thereof, wherein R^(6a) is H.
 43. The compound of any one of claims1 to 42, or a pharmaceutically acceptable salt thereof, wherein m is 0.44. The compound of any one of claims 1 to 42, or a pharmaceuticallyacceptable salt thereof, wherein m is 1 and R^(6b) is selected from thegroup consisting of F, C₁₋₄ alkyl, O—R^(q), C₁₋₄ haloalkyl andNR^(q)R^(r), wherein each R^(q) and R^(r) is independently selected fromhydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl.
 45. The compound of any one ofclaims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein mis 1 and R^(6b) is F.
 46. The compound of any one of claims 1 to 42, ora pharmaceutically acceptable salt thereof, wherein

is


47. The compound of any one of claims 1 to 42, or a pharmaceuticallyacceptable salt thereof, wherein

is


48. The compound of any one of claims 1 to 46, or a pharmaceuticallyacceptable salt thereof wherein R⁴ is optionally substituted with 1 to 2R^(4a), wherein each R^(4a) is independently selected from the groupconsisting of halogen, —CN, —R^(m), —CO₂R^(n), —CONR^(n)R^(p),—C(O)R^(n), —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),—NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), and —S(O)₂NR^(n)R^(p).49. The compound of any one of claims 1 to 46, or a pharmaceuticallyacceptable salt thereof wherein R⁴ is selected from the group consistingof O—C₁₋₄ alkyl, O—C₁₋₆ alkyl-CN, phenyl, pyridinyl, —O—C₁₋₂alkyl-pyridinyl, —O—C₁₋₂ alkyl-pyrimidinyl, —O—C₁₋₂ alkyl-pyridazinyl,and —O—C₁₋₂ alkyl-phenyl, each of which is optionally substituted with 1to 2 R^(4a) wherein each R^(4a) is independently selected from the groupconsisting of halogen, —CN, —CO₂R^(n), —NR^(n)R^(p), and —OR^(n).
 50. Acompound of claim 1, or a pharmaceutically acceptable salt thereof,selected from Table 1 and having an activity of ++ or +++.
 51. Apharmaceutical composition comprising a compound of any one of claims 1to 50, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 52. The pharmaceuticalcomposition of claim 51, further comprising one or more additionaltherapeutic agents.
 53. The pharmaceutical composition of claim 52,wherein the one or more additional therapeutic agent is selected fromthe group consisting of an antimicrobial agent, an antiviral agent, acytotoxic agent, a gene expression modulatory agent, a chemotherapeuticagent, an anti-cancer agent, an anti-angiogenic agent, animmunotherapeutic agent, an anti-hormonal agent, an anti-fibrotic agent,radiotherapy, a radiotherapeutic agent, an anti-neoplastic agent, and ananti-proliferation agent.
 54. A method of modulating an immune responsemediated by the PD-1 signaling pathway in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound of any one of claims 1 to 50, or a pharmaceutically acceptablesalt thereof or a composition of any one of claims 51 to
 53. 55. Amethod of enhancing, stimulating, modulating and/or increasing theimmune response in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a compound of anyone of claims 1 to 50, or a pharmaceutically acceptable salt thereof ora composition of any one of claims 51 to
 53. 56. A method of inhibitinggrowth, proliferation, or metastasis of cancer cells in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of any one of claims 1 to 50, or apharmaceutically acceptable salt thereof or a composition of any one ofclaims 51 to
 53. 57. A method of treating a subject suffering from orsusceptible to a disease or disorder mediated by the PD-1 signalingpathway, comprising administering to the subject a therapeuticallyeffective amount of a compound of any one of claims 1 to 50, or apharmaceutically acceptable salt thereof or a composition of any one ofclaims 51 to
 53. 58. The method of any one of claims 54 to 57, whereinthe subject suffers from a disease or disorder selected from the groupconsisting of an infectious disease, a bacterial infectious disease, aviral infectious disease a fungal infectious disease, a solid tumor, ahematological malignancy, an immune disorder, an inflammatory disease,and cancer.
 59. The method of claim 57, wherein the disease or disorderis selected from the group consisting of melanoma, glioblastoma,esophagus tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma,lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuselarge B-cell lymphoma, primary mediastinal large B-cell lymphoma,prostate cancer, castration-resistant prostate cancer, chronicmyelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma,synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of softtissue, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymusneoplasm, cancer of the thyroid gland, cancer of the parathyroid gland,uterine cancer, cancer of the adrenal gland, liver infection, Merkelcell carcinoma, nerve tumor, follicle center lymphoma, colon cancer,Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acuteleukemias including acute myeloid leukemia, chronic myeloid leukemia,acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiplemyeloma, ovary tumor, myelodysplastic syndrome, cutaneous or intraocularmalignant melanoma, renal cell carcinoma, small-cell lung cancer, lungcancer, mesothelioma, breast cancer, squamous non-small cell lung cancer(SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastriccancer, hepatocellular carcinoma, pancreatic carcinoma, pancreaticcancer, Pancreatic ductal adenocarcinoma, squamous cell carcinoma of thehead and neck, cancer of the head or neck, gastrointestinal tract,stomach cancer, HIV, Hepatitis A, Hepatitis B, Hepatitis C, hepatitis D,herpes viruses, papillomaviruses, influenza, bone cancer, skin cancer,rectal cancer, cancer of the anal region, testicular cancer, carcinomaof the fallopian tubes, carcinoma of the endometrium, carcinoma of thecervix, carcinoma of the vagina, carcinoma of the vulva, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the urethra, cancer of the penis, cancer of thebladder, cancer of the kidney, cancer of the ureter, carcinoma of therenal pelvis, neoplasm of the central nervous system (CNS), tumorangiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma,epidermoid cancer, abestosis, carcinoma, adenocarcinoma, papillarycarcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cellcarcinoma, transitional cell carcinoma, choriocarcinoma, seminoma,embryonal carcinoma, wilm's tumor, pleomorphic adenoma, liver cellpapilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma,leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma,lipoma and fibroma.
 60. The method of any one of claims 54 to 59,further comprising administering to the subject a therapeuticallyeffective amount of one or more additional therapeutic agents.
 61. Themethod of claim 60, wherein the one or more additional therapeuticagents is selected from the group consisting of an antimicrobial agent,an antiviral agent, a cytotoxic agent, a gene expression modulatoryagent, a chemotherapeutic agent, an anti-cancer agent, ananti-angiogenic agent, an immunotherapeutic agent, an anti-hormonalagent, an anti-fibrotic agent, radiotherapy, a radiotherapeutic agent,an anti-neoplastic agent, and an anti-proliferation agent.